Substituted 7-Azabicycles And Their Use As Orexin Receptor Modulators

ABSTRACT

The present invention is directed to compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyl, thiazolyl, isoxazolyl, pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl; R 1  is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino; R 2  is H, alkyl, alkoxy, hydroxyalkylene, or halo; Z is NH, N-alkyl, or O; R 5  is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo; and n is 0 or 1. Methods of making the compounds of Formula I are also described. The invention also relates to pharmaceutical compositions comprising compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/718,327, filed May 21, 2015, which is a divisional of U.S. patentapplication Ser. No. 14/206,764, filed Mar. 12, 2014, now U.S. Pat. No.9,062,078, which claims the benefit of U.S. Provisional PatentApplication No. 61/780,428, filed Mar. 13, 2013, the entire disclosuresof which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention is directed to substituted 7-azabicycliccompounds, pharmaceutical compositions comprising them, methods ofmaking them, and methods of using them for the modulation of the orexinreceptor for the treatment of disease states, disorders, and conditionsmediated by orexin receptor activity.

BACKGROUND

Orexin/hypocretin signaling is mediated by two receptors and two peptideagonists. The peptides (orexin-A and orexin-B) are cleavage products ofthe same gene, pre-pro orexin. In the central nervous system, neuronsproducing pre-pro orexin are found solely in the perifornical nucleus,the dorsal hypothalamus, and the lateral hypothalamus (Peyron et al.,1998, J. Neurosci. 18: 9996-10015). Orexigenic cells in these regionsproject to many areas of the brain, extending rostrally to the olfactorybulbs and caudally to the spinal cord (Van den Pol, 1999, J. Neurosci.19: 3171-3182).

The orexins bind to two high affinity receptors, referred to as orexin-1and orexin-2 receptors. Orexin-1 and orexin-2 receptors areG-protein-coupled, seven transmembrane receptors that share over 64%amino acid sequence identity with one another. Both receptors aregenerally excitatory, the common cellular response to orexin-inducedreceptor activation being increases in intracellular calcium. Homologybetween the species orthologs is high and there are no knownpharmacological differences. Orexin-A and -B are usually consideredequal ligands for orexin-2 receptor but orexin-B is thought to be 5- to100-fold weaker ligand than orexin-A at the orexin-1 receptor (Sakuraiet al., 1998, Cell 92: 573-585; Ammoun et al., 2003, J. Pharmacol. Exp.Ther. 305: 507-514).

Many regions of the brain have fairly selective expression of theorexin-1 or orexin-2 receptors (Marcus et al., 2001, 1 Comp Neurology435, 6-25; Trivedi et al., 1998, FEBS Letters, 438, 71-75). Orexin-1receptors are selective for the limbic system (bed nucleus of the striaterminalis and amygdala), cingulate cortex and noradrenergic neurons inthe locus coeruleus. Conversely, the orexin-2 receptor is almost theexclusive orexin receptor in the histaminergic neurons in thetuberomammilary nucleus which play a critical role in wake promotion; inparaventricular neurons and the parabrachial nucleus. In other brainregions like the dorsal raphe, the ventral tegmental area or theprefontal cortex both receptors are coexpressed.

The broad CNS distribution of cells producing orexin, as well as cellsexpressing the orexin receptors, suggests involvement of orexin in anumber of physiological functions, including feeding and metabolism,regulation of wakefulness and sleep, sympathetic activation and stressresponse (de Lecea, 2012, Progress in Brain Research, 198, 15-24;Kukkonen, 2013, Am J. Physiol. Cell Physiol., 304, C2-C32). Orexin alsoplays a key role regulating motivation and reward associated with foodintake and with drugs of abuse (Mahler et al., 2012, Progress in BrainResearch, 198, 79-121).

Several lines of evidence indicate that the orexin system is animportant modulator of arousal. Rodents administered orexinintracerebroventricularly spend more time awake (Piper et al., 2000, J.Neurosci. 12: 726-730. Orexin-mediated effects on arousal have beenlinked to orexin neuronal projections to histaminergic neurons in thetuberomammillary nucleus (Yamanaka et al., 2002, Biochem. Biophys. Res.Comm. 290: 1237-1245). Rodents whose pre-pro orexin gene has beenknocked out, or whose orexigenic neurons have been killed, displayaltered sleep/wake cycles similar to narcolepsy (Chemelli et al., 1999,Cell 98: 437-451; Hara et al., 2001, Neuron 30: 345-354). Dog models ofnarcolepsy have been shown to have mutant or non-functional orexin-2receptors (Lin et al., 1999, Cell 98: 365-376). Orexin signaling as atarget for sleep-promoting therapies was further validated clinically byfindings of attenuated orexin levels and loss of orexinergic neurons inhuman narcoleptic patients (Mignot et al., 2001, Am. J. Hum. Genet. 68:686-699; Minot & Thorsby, 2001, New England J. Med. 344: 692) or, inrare cases, to mutations in the orexin-2 gene (Peyron et al., 2000,Nature Med. 6: 991-997). Disorders of the sleep-wake cycle are thereforelikely targets for orexin-2 receptor modulator activity. Examples ofsleep-wake disorders that may be treated by agonists or other modulatorsthat up-regulate orexin-2 receptor-mediated processes includenarcolepsy, jet lag (sleepiness) and sleep disorders secondary toneurological disorders such as depression. Examples of disorders thatmay be treated by antagonists or other modulators that down-regulateorexin-2 receptor-mediated processes include insomnia, restless legsyndrome, jet lag (wakefulness) and sleep disorders secondary toneurological disorders such as mania, schizophrenia, pain syndromes andthe like.

Evidence has accumulated to demonstrate a clear involvement of orexinsignaling in reward pathways associated with drug dependence (Mahler etal., 2012, Progress in Brain Research, 198, 79-121). Orexinergic neuronssend projections to the ventral tegmental area and other brain regionsinvolved in reward processing. Orexin ligands mediate reward behavior,and antagonizing these effects with a selective orexin-1 receptorantagonist in various preclinical model of addiction has suggested thatthese actions are mediated through orexin-1 receptor. Specifically, aselective orexin-1 antagonist attenuates morphine conditioned placepreference and reinstatement (Harris et al., 2005, Nature, 437,556-5599; Narita et al., 2006, J Neurosci., 26, 398-405; Harris et al.,2007, Behav Brain Res, 183, 43-51), stress-induced cocainereinstatement, cocaine-induced behavioral and synaptic plasticity(Borgland et al., 2006, Neuron, 49, 589-601), and intake and cue andstress-induced reinstatement of ethanol (Lawrence et al., 2006, Br JPharmacol, 148, 752-759), in addition to attenuating precipitatedmorphine withdrawal (Sharf et al., 2008, Biol Psychiatry, 64, 175-183)and nicotine self-administration (Hollander et al., 2008, Proc Natl AcadSci USA., 105, 19480-19485). Another recent study has also suggested arole for OX2R (Shoblock et al., 2011, Psychopharmacology, 215, 191-203).

Orexin's role in more complex emotional behavior is also emerging(Johnson et al., 2012, Progress in Brain Research, 198, 133-161).Changes in orexin levels in patients with panic and posttraumatic stressdisorders have been noted as have changes in the prevalence of anxietybehaviors in narcoleptic patients (Johnson et al., 2010, NatureMedicine, 16, 111-115; Fortuyn et al., 2010, General HospitalPsychiatry, 32, 49-56; Strawn et al., 2010, Psychoneuroendocrinology,35, 1001-1007). Lactate infusion or acute hypercapnia, which causespanic in humans, and are used as an animal model of panic, activatesorexin neurons in the perifornical hypothalamus. This activationcorrelates with anxiety in the social interaction test or open fieldtest. Blocking orexin signaling with either siRNA or selective orexin-1receptor antagonists attenuates panic-like responses to lactate (Johnsonet al., 2010, Nature Medicine, 16, 111-115; Johnson et al., 2012,Neuropsychopharmacology, 37, 1911, 1922).

Cerebral spinal fluid (CSF) levels of orexin are lower in depressed orsuicidal patients, and the level of orexin inversely correlates withillness severity (Brundin et al., 2007, EuropeanNeuropsychopharmacology, 17, 573-579; Salomon et al., 2003, BiolPsychiatry, 54, 96-104). A positive correlation between orexin-1receptor mRNA in the amygdala and depressive behavior in the forced swimtest in mice has been reported (Arendt, 2013, Behavioral Neuroscience,127, 86-94).

The orexin system also interacts with brain dopamine systems.Intracerebroventricular injections of orexin in mice increase locomotoractivity, grooming and stereotypy; these behavioral effects are reversedby administration of D2 dopamine receptor antagonists (Nakamura et al.,2000, Brain Res. 873: 181-187). Therefore, orexin receptor modulatorsmay be useful to treat various neurological disorders; e.g., agonists orup-regulators to treat catatonia, antagonists or down-regulators totreat Parkinson's disease, Tourette's syndrome, anxiety, delirium anddementias.

Orexins and their receptors have been found in both the myenteric andsubmucosal plexus of the enteric nervous system, where orexins have beenshown to increase motility in vitro (Kirchgessner & Liu, 1999, Neuron24: 941-951) and to stimulate gastric acid secretion in vitro (Takahashiet al., 1999, Biochem. Biophys. Res. Comm. 254: 623-627). Orexin effectson the gut may be driven by a projection via the vagus nerve (van denPol, 1999, supra), as vagotomy or atropine prevent the effect of anintracerebroventricular injection of orexin on gastric acid secretion(Takahashi et al., 1999, supra). Orexin receptor antagonists or otherdown-regulators of orexin receptor-mediated systems are thereforepotential treatments for ulcers, irritable bowel syndrome, diarrhea andgastroesophageal reflux.

Body weight may also be affected by orexin-mediated regulation ofappetite and metabolism. Some effects of orexin on metabolism andappetite may be mediated in the gut, where, as mentioned, orexins altergastric motility and gastric acid secretion. Orexin antagoniststherefore are likely to be useful in treatment of overweight or obesityand conditions related to overweight or obesity, such as insulinresistance/type II diabetes, hyperlipidemia, gallstones, angina,hypertension, breathlessness, tachycardia, infertility, sleep apnea,back and joint pain, varicose veins and osteoarthritis. Conversely,orexin agonists are likely to be useful in treatment of underweight andrelated conditions such as hypotension, bradycardia, amenorrhea andrelated infertility, and eating disorders such as anorexia and bulimia.

Intracerebroventricularly administered orexins have been shown toincrease mean arterial pressure and heart rate in freely moving (awake)animals (Samson et al., 1999, Brain Res. 831: 248-253; Shirasaka et al.,1999, Am. J. Physiol. 277: R1780-R1785) and in urethane-anesthetizedanimals (Chen et al., 2000, Am. J. Physiol. 278: R692-R697), withsimilar results. Orexin receptor agonists may therefore be candidatesfor treatment of hypotension, bradycardia and heart failure relatedthereto, while orexin receptor antagonists may be useful for treatmentof hypertension, tachycardia and other arrhythmias, angina pectoris andacute heart failure.

From the foregoing discussion, it can be seen that the identification oforexin receptor modulators, will be of great advantage in thedevelopment of therapeutic agents for the treatment of a wide variety ofdisorders that are mediated through these receptor systems.

SUMMARY

The present invention is directed to compounds of Formula I:

wherein ring A is phenyl, naphthalenyl, pyridyl, quinolinyl,isoquinolinyl, imidazopyridyl, furanyl, thiazolyl, isoxazolyl,pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl; R₁ is H,alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl,isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl,pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, ordialkylamino; R₂ is H, alkyl, alkoxy, hydroxyalkylene, or halo; Z is NH,N-alkyl, or O; R₅ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,quinazolinyl, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl,triazolopyrazinyl, optionally substituted with a one or two substituentsindependently selected from the group consisting of alkyl, alkoxy, orhalo; and n is 0 or 1. Enantiomers and diastereomers of the compounds ofFormula I are also described, as well as the pharmaceutically acceptablesalts.

Methods of making the compounds of Formula I are also described. Theinvention also relates to pharmaceutical compositions comprisingcompounds of Formula I. Methods of using the compounds of the inventionare also within the scope of the invention.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me) ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples. Alkyl groups of the invention can beoptionally substituted with, for example, one or more halogen atoms. Oneexemplary substituent is fluoro. Preferred substituted alkyl groups ofthe invention include trihalogenated alkyl groups such astrifluoromethyl groups.

Alkyl groups of the invention can also refer to “cycloalkyl” moieties.Cycloalkyl refers to monocyclic, non-aromatic hydrocarbon groups havingfrom 3 to 7 carbon atoms. Examples of cycloalkyl groups include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-methylcyclopropyl, 2-methylcyclopentyl, and the like.

The term “alkoxy” includes a straight chain or branched alkyl group witha terminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. Alkoxy groups of the inventions can be optionallysubstituted with, for example, one or more halogen atoms (haloalkoxy).One exemplary substitutent is fluoro. Preferred substituted alkoxygroups of the invention are substituted with one, two, or three halogenatoms, for example, —OCHCF₂.

The term “amino” represents NH₂. The term “dialkylamino” represents themoiety wherein each H of the amino group is replaced by an alkyl group.These alkyl groups ca be the same or different. Preferred alkyl groupsare the C₁₋₆alkyl groups. Examples of dialkyl amino groups includedimethylamino, diethylamino, diisopropylamino, and the like. Otherexamples include methylethylamino, methylisopropylamino, and the like.

The term “aryl ring” represents” a mono- or bi-cyclic aromatic,hydrocarbon ring structure. Aryl rings can have 6 or 10 carbon atoms inthe ring.

The term “benzimidazolyl” represents the following moiety:

The benzimidazolyl moiety can be attached through any one of the 1-, 2-,3-, 4-, 5-, 6-, or 7-position atoms.

The term “benzoxazolyl” represents the following moiety:

The benoxazolyl moiety can be attached through any one of the 2-, 4-,5-, 6-, or 7-position carbon atoms.

The term “furanyl” represents the following moiety:

The furanyl moiety can be attached through any one of the 2-, 3-, 4-, or5-position carbon atoms.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “heteroaryl ring” represents a mono- or bicyclic aromatic ringstructure including carbon atoms as well as up to four heteroatomsselected from nitrogen, oxygen, and sulfur. Heteroaryl rings can includea total of 5, 6, 9, or 10 ring atoms.

The term “hydroxyalkylene” represents an alkyl group, terminallysubstituted with OH. Examples of hydroxyalkylene moieties include—CH₂—OH, —CH₂CH₂—OH, —CH₂CH₂CH₂—OH, and the like.

The term “imidazopyridyl” represents the following moiety:

The imidazopyridyl moiety can be attached through any one of the 2-, 3-,4-, 5-, 6-, or 7-position carbon atoms.

The term “imidazopyrazinyl” represents the following moiety:

The imidazopyrazinyl moiety can be attached through any one of the 2-,5-, or 6-position carbon atoms.

The term “imidazothiazolyl” represents the following moiety:

The imidazothiazolyl moiety can be attached through any one of the 2-,3-, 5-, or 6-position carbon atoms.

The term “indazolyl” represents the following moiety:

The indazolyl moiety can be attached through any one of the 1-, 3-, 4-,5-, 6-, or 7-position atoms.

The term “isoquinolinyl” represents the following moiety:

The isoquinolinyl moiety can be attached through any one of the 1-, 3-,4-, 5-, 6-, 7-, or 8-position carbon atoms.

The term “isoxazolyl” represents the following moiety:

The isoxazolyl moiety can be attached through any one of the 3-, 4-, or5-position carbon atoms. Isoxazolyl groups of the invention can beoptionally substituted with, for example, one or two alkyl groups, forexample, one or two methyl groups.

The term “naphthalenyl” represents the following moiety:

The naphthalenyl moiety can be attached through any one of the 1-, 2-,3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms.

The term “morpholinyl” represents the following moiety:

The 4-position nitrogen atom may be substituted with H or alkyl, forexample methyl. The 4-position nitrogen can also be protected with anitrogen protecting group such as a butyl-oxycarbonyl (-Boc). Themorpholinyl moiety can be attached through any one of the 2-, 3-, 4-,5-, or 6-position atoms.

The term “oxazolyl” represents the following moiety:

The oxazolyl moiety can be attached through any one of the carbon atoms.Oxazolyl groups of the invention can be optionally substituted with, forexample, one or two alkyl groups, for example, one or two methyl groups.

The term “oxadiazolyl” represents a 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, or 1,3,4-oxadiazole moiety:

The oxadiazolyl moieties can be attached through any one of the carbonor nitrogen atoms. Within the scope of the invention, “oxadiazolyl”groups can be substituted with an alkyl group, preferably a methylgroup.

The term “phenyl” represents the following moiety:

Phenyl groups of the inventions can be optionally substituted with, forexample, one or more halogen atoms (halo-phenyl). Exemplary substituentsare fluoro, bromo, and chloro. Preferred substituted phenyl groups ofthe invention are substituted with one, two, or three halogen atoms.

The term “pyridyl” represents the following moiety:

The pyridyl moiety can be attached through any one of the 2-, 3-, 4-,5-, or 6-position carbon atoms. Pyridyl groups of the invention can beoptionally substituted with, for example, one or more alkyl groups, forexample, one or two methyl groups.

The term “piperazinyl” represents the following moiety:

The piperazinyl moiety can be attached through any one of the 1-, 2-,3-, 4-, 5-, or 6-position atoms. Any one of the nitrogen atoms of thepiperazinyl moiety can be substituted with H or alkyl, for example,methyl.

The term “pyrimidinyl” represents the following moiety:

The pyrimidinyl moiety can be attached through any one of the 2-, 4-,5-, or 6-position carbon atoms. Within the scope of the invention,“pyrimidinyl” groups of the invention can be substituted with halogen,for example fluoro.

The term “pyrazinyl” represents the following moiety:

The pyrazinyl moiety can be attached through any one of the 2-, 3-, 5-,or 6-position carbon atoms.

The term “pyridazinyl” represents the following moiety:

The pyridazinyl moiety can be attached through any one of the 3-, 4-,5-, or 6-position carbon atoms.

The term “pyrazolyl” represents the following moiety:

The pyrazolyl moiety can be attached through any one of the 1-, 2-, 3-,4-, or 5-position carbon atoms. Pyrazolyl groups of the invention can beoptionally substituted with, for example, one or two alkyl groups, forexample, one or two methyl groups.

The term “pyrrolidinyl” represents the following moiety:

The pyrrolidinyl moiety can be attached through any one of the 1-, 2-,3-, 4-, or 5-position atoms. When the pyrrolidinyl moiety is notattached through the 1-position nitrogen, the nitrogen can besubstituted with H or alkyl, for example methyl.

The term “quinolinyl” represents the following moiety:

The quinolinyl moiety can be attached through any one of the 2-, 3-, 4-,5-, 6-, 7-, or 8-position carbon atoms.

The term “quinoxalinyl” represents the following moiety:

The quinoxalinyl moiety can be attached through any one of the 2-, 3-,5-, 6-, 7-, or 8-position carbon atoms.

The term “quinazolinyl” represents the following moiety:

The quinoxalinyl moiety can be attached through any one of the 2-, 4-,5-, 6-, 7-, or 8-position carbon atoms.

The term “thiazolyl” represents the following moiety:

The thiazolyl moiety can be attached through any one of the 2-, 4-, or5-position carbon atoms.

The term “thiophenyl” represents the following moiety:

The thiophenyl moiety can be attached through any one of the 2-, 3-, 4-,or 5-position carbon atoms.

The term “triazolopyrazinyl” represents the following moiety:

The triazolopyrazinyl moiety can be attached through any one of the 1-,3-, 4-, 5-, 6-, or 7-position atoms.

The term “triazolyl” represents a 1,2,3-triazole or a 1,2,4-triazolemoiety:

The triazolyl moieties can be attached through any one of their atoms.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered. A “pharmaceutically acceptable excipient” refers to asubstance that is non-toxic, biologically tolerable, and otherwisebiologically suitable for administration to a subject, such as an inertsubstance, added to a pharmacological composition or otherwise used as avehicle, carrier, or diluent to facilitate administration of agent andthat is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Compounds of the present invention,” and equivalent expressions, aremeant to embrace compounds of the Formula (I) as described herein, whichexpression includes the pharmaceutically acceptable salts, and thesolvates, e.g., hydrates, where the context so permits. Similarly,reference to intermediates, whether or not they themselves are claimed,is meant to embrace their salts, and solvates, where the context sopermits.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can be radiolabeled, that is, contain one or morenon-radioactive isotopes, such as for example, deuterium (²H or D),carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will be understoodthat, in a compound where such isotopic substitution is made, thefollowing atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art. Likewise, the invention may include thepreparation of isotopic variants with radioisotopes, in the instance forexample, where the resulting compounds may be used for drug and/orsubstrate tissue distribution studies. Radiolabeled compounds of theinvention can be used in diagnostic methods such as Single-photonemission computed tomography (SPECT). The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for their easeof incorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds of the invention, radioactive ornot, are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers.”

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

Compounds of the invention may also exist as “rotamers,” that is,conformational isomers that occur when the rotation leading to differentconformations is hindered, resulting a rotational energy barrier to beovercome to convert from one conformational isomer to another.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

The present invention is directed to compounds of Formula I:

wherein

ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl,imidazopyridyl, furanyl, thiazolyl, isoxazolyl, pyrazolyl,imidazothiazolyl, benzimidazolyl, or indazolyl;

R₁ is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl,oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl,morpholinyl, or dialkylamino;

R₂ is H, alkyl, alkoxy, hydroxyalkylene, or halo;

Z is NH, N-alkyl, or O;

R₅ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyl,quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, ortriazolopyrazinyl, optionally substituted with a one or two substituentsindependently selected from the group consisting of alkyl, alkoxy, orhalo; and

n is 0 or 1.

Enantiomers and diastereomers of the compounds of Formula I are alsowithin the scope of the invention. Also within the scope of theinvention are the pharmaceutically acceptable salts of the compounds ofFormula I, as well as the pharmaceutically acceptable salts of theenantiomers and diastereomers of the compounds of Formula I.

In preferred embodiments of the invention, Z is NH. In otherembodiments, Z is N-alkyl, preferably N—C₁₋₆alkyl, with N—CH₃ beingparticularly preferred.

In alternative embodiments, N is O.

In preferred embodiments of the invention, ring A is a heteroaryl ring.Preferably, ring A is furanyl, which can be attached to the compounds ofFormula I through any available atom, preferably the 2-position carbonatom. In other embodiments, ring A is thiazolyl, which can be attachedto the compounds of Formula I through any available atom, preferably the4-position carbon atom.

In still other embodiments, ring A is isoxazolyl, which can be attachedto the compounds of Formula I through any available atom, preferably the4-position carbon atom.

In yet other embodiments, ring A is pyrazolyl, which can be attached tothe compounds of Formula I through any through any available atom,preferably the 3- or 4-position carbon atoms.

Also preferred are embodiments wherein ring A is imidazothiazolyl, whichcan be attached to the compounds of Formula I through any availableatom, preferably the 5-position carbon atom.

In certain embodiments of the invention, ring A is benzimidazolyl, whichcan be attached to the compounds of Formula I through any availableatom, preferably the 2-position carbon atom.

In other embodiments of the invention, ring A is indazolyl, which can beattached to the compounds of Formula I through any available atom,preferably the 3-position carbon atom.

In yet other embodiments, ring A is imidazopyridyl, which can beattached to the compounds of Formula I through any available atom,preferably the 4-, or 7-position carbon atom

In still other embodiments, ring A is quinolinyl, which can be attachedto the compounds of Formula I through any available carbon atom,preferably the 5- or 8-position carbon atom.

In other embodiments, ring A is isoquinolinyl, which can be attached tothe compounds of Formula I through any available carbon atom, preferablythe 4-position carbon atom.

In certain embodiments, ring A is pyridyl, which can be attached to thecompounds of Formula I through any available carbon atom, preferably the2-, 3-, or 4-position carbon atom.

In some embodiments, ring A can be an aryl ring. In certain embodiments,ring A is phenyl. In other embodiments, ring A is naphthalenyl, whichcan be attached to the compounds of Formula I through any availablecarbon atom, preferably the 1-position carbon atom.

In preferred embodiments of the invention, R₁ is H. In otherembodiments, R₁ is alkyl, preferably a C₁₋₆alkyl, for example, methyl.

In still other embodiments, R₁ is alkoxy, preferably a C₁₋₆alkoxy suchas methoxy or ethoxy. Alternatively, R₁ is a substituted alkoxy,preferably substituted with one or more halo such as F, Cl, or Br. Onepreferred haloalkoxy is difluoromethoxy.

In other embodiments, R₁ is hydroxalkylene, for example,hydroxyC₁₋₆alkylene such as —CH₂—OH or —CH₂CH₂—OH. In yet otherembodiments, R₁ is OH.

In other preferred embodiments, R₁ is halo, that is, any one of F, Cl,Br, or I, with F, Cl, or Br being particularly preferred.

In still other embodiments, R₁ is phenyl. In some embodiments, thephenyl can be substituted with at least one halo, for example, phenylsubstituted with at least one of F, Cl, or Br.

In certain embodiments, R₁ is triazolyl, with 1,2,3-triazolyl beingpreferred. The triazolyl can be attached through any available atom. Inpreferred embodiments, the 1,2,3-triazolyl is attached through the2-position nitrogen atom. In other embodiments, the 1,2,3-triazolyl isattached through the 1-position nitrogen atom.

In yet other embodiments, R₁ is oxazolyl, which can be attached throughany available atom, preferably attached through the 2-position carbon.In some embodiments, the oxazolyl can be substituted with alkyl, forexample, a C₁₋₆alkyl such as methyl.

In other embodiments, R₁ is isoxazolyl, which can be attached throughany available atom. In some embodiments, the isoxazolyl can besubstituted with alkyl, for example, a C₁₋₆alkyl such as methyl.

In still other embodiments, R₁ is pyridyl, which can be attached throughany available carbon atom. In some embodiments, the pyridyl can besubstituted with at least one alkyl, for example, C₁₋₆alkyl such asmethyl.

In certain embodiments, R₁ is pyrimidinyl, which can be attached throughany available carbon atom. In other embodiments, R₁ is pyrazinyl, whichcan be attached through any available carbon atom. In yet otherembodiments, R₁ is pyridazinyl, which can be attached through anyavailable carbon atom.

In other embodiments, R₁ is piperazinyl which can be attached throughany available atom. In some embodiments, one or both nitrogen atoms ofthe piperazinyl may be substituted with H or alkyl, for example,C₁₋₆alkyl such as methyl.

In still other embodiments, R₁ is morpholinyl, which can be attachedthrough any available atom. In some embodiments, the nitrogen of themorpholinyl may be substituted with H or alkyl, for example, C₁₋₆alkylsuch as methyl.

In yet other embodiments, R₁ is pyrrolidinyl, which can be attachedthrough any available atom. In some embodiments, the nitrogen of thepyrrolidinyl may be substituted with H or alkyl, for example, C₁₋₆alkylsuch as methyl.

In other embodiments, R₁ is dialkylamino, for example, dimethylamino,diethylamino, or methylethylamino.

In other embodiments, R₁ is pyrazolyl, which can be attached through anyavailable atom. In some embodiments, the pyrazolyl can be substitutedwith one or two alkyl, for example, C₁₋₆alkyl such as methyl.

In yet other embodiments, R₁ is oxadiazolyl, which can be a1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or1,3,4-oxadiazolyl. Preferably, the oxadiazolyl is 1,2,4-oxadiazolyl. Theoxadiazolyl can be attached through any available atom. In someembodiments, the oxadiazolyl can be substituted with alkyl, for example,C₁₋₆alkyl such as methyl.

In still other embodiments, R₁ is thiophenyl, which can be attachedthrough any available carbon atom.

In preferred embodiments of the invention, R₂ is H. In otherembodiments, R₂ is alkyl, for example, C₁₋₆alkyl such as methyl orethyl. In yet other embodiments, R₂ is alkoxy, for example, C₁₋₆alkoxysuch as methoxy or ethoxy. In other embodiments, R₂ is hydroxylalkene,for example, —CH₂—OH or CH₂CH₂—OH. In still other embodiments, R₂ ishalo, preferably, any one of F, Cl, or Br.

In exemplary embodiments of the invention, ring A is

wherein

-   -   X is CR₆, N, or NR₆;    -   Y is CR₇, N, or NR₇;    -   R₆ is H, alkyl, alkoxy, OH, halo, triazolyl, oxazolyl,        oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,        pyrazolyl, or thiophenyl;    -   R₇ is H, alkyl, alkoxy, or halo;    -   R₃ is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl,        triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl,        pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl,        pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino;    -   R₄ is H, alkyl, alkoxy, or halo;    -   or        -   R₆ and R₇, together with the atoms to which they are            attached, form a 5- or 6-membered heteroaryl ring optionally            substituted with alkyl; or        -   R₃ and R₄, together with the atoms to which they are            attached, form a 6-membered aryl or 6-membered heteroaryl            ring; or        -   R₇ and R₄, together with the atoms to which they are            attached, form a 6-membered aryl or 6-membered heteroaryl            ring.

In certain of these embodiments, X is CR₆ and Y is CR₇.

In other of these embodiments, X is CR₆ and Y is N.

In still other of these embodiments, X is N and Y is CR₇.

In those embodiments wherein X is CR₆, for example those embodimentswherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is H.Alternatively, R₆ is alkyl, for example, C₁₋₆alkyl such as methyl orethyl.

In other of these embodiments, R₆ is alkoxy, for example, C₁₋₆alkoxysuch as methoxy or ethoxy.

In still other of these embodiments, R₆ is OH.

In yet other of these embodiments, R₆ is halo, preferably, any one of F,Cl, or Br.

In those embodiments wherein X is CR₆, for example those embodimentswherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is triazolylwith 1,2,3-triazolyl being preferred. The triazolyl can be attachedthrough any available atom. In preferred embodiments, the1,2,3-triazolyl is attached through the 2-position nitrogen atom. Inother embodiments, the 1,2,3-triazolyl is attached through the1-position nitrogen atom.

In those embodiments wherein X is CR₆, for example those embodimentswherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is oxazolyl,which can be attached through any available atom. In some embodiments,the oxazolyl can be substituted with alkyl, for example, C₁₋₆alkyl suchas methyl.

In those embodiments wherein X is CR₆, for example those embodimentswherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is oxadiazolyl,which can be a 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,or 1,3,4-oxadiazolyl. Preferably, the oxadiazolyl is 1,2,4-oxadiazolyl.The oxadiazolyl can be attached through any available atom. In someembodiments, the oxadiazolyl can be substituted with alkyl, for example,C₁₋₆alkyl such as methyl.

In those embodiments wherein X is CR₆, for example those embodimentswherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is pyrazolyl,which can be attached through any available atom. In some embodiments,the pyrazolyl can be substituted with one or two alkyl, for example,C₁₋₆alkyl such as methyl.

In those embodiments wherein X is CR₆, for example those embodimentswherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is thiophenyl,which can be attached through any available atom.

In those embodiments wherein X is CR₆, for example those embodimentswherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is pyridyl,which can be attached through any available atom. In some embodiments,the pyridyl can be substituted with one or more alkyl, for example,C₁₋₆alkyl such as methyl. One exemplary substituted pyridyl ismethyl-pyridyl.

In those embodiments wherein X is CR₆, for example those embodimentswherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is pyrimidinyl,which can be attached through any available atom. In other embodiments,R₆ is pyrazinyl, which can be attached through any available atom. Instill other embodiments, R₆ is pyridazinyl, which can be attachedthrough any available atom.

In preferred embodiments wherein Y is CR₇, for example, thoseembodiments wherein X is CR₆ and Y is CR₇ or X is N and Y is CR₇, R₇ isH. In other embodiments, R₇ is alkyl, for example, C₁₋₆alkyl such asmethyl or ethyl.

In those embodiments wherein Y is CR₇, for example, those embodimentswherein X is CR₆ and Y is CR₇ or X is N and Y is CR₇, R₇ is alkoxy, forexample, C₁₋₆alkoxy such as methoxy or ethoxy. In other embodiments, thealkoxy is substituted with, for example, one or more halo. One preferredsubstituted alkoxy is difluoromethoxy.

In those embodiments wherein Y is CR₇, for example, those embodimentswherein X is CR₆ and Y is CR₇ or X is N and Y is CR₇, R₇ is halo,preferably one of F, Cl, or Br.

In some embodiments, X is NR₆ and Y is CR₇.

In other embodiments, X is CR₆ and Y is NR₇.

In those embodiments wherein X is NR₆ and Y is CR₇ or X is CR₆ and Y isNR₇, R₆ and R₇, together with the atoms to which they are attached, forma 5-membered heteroaryl ring. These 5-membered rings can be optionallysubstituted with alkyl, for example C₁₋₆alkyl such as methyl.

In those embodiments wherein X is NR₆ and Y is CR₇ or X is CR₆ and Y isNR₇, R₆ and R₇, together with the atoms to which they are attached, forma 6-membered heteroaryl ring. These 5-membered rings can be optionallysubstituted with alkyl, for example C₁₋₆alkyl such as methyl.

In those embodiments wherein Y is CR₇ or NR₇, R₇ and R₄, together withthe atoms to which they are attached, form a 6-membered aryl ring.Alternatively, R₇ and R₄, together with the atoms to which they areattached, form a 6-membered heteroaryl ring.

In preferred embodiments, R₃ is H. In other embodiments, R₃ is alkyl,for example, C₁₋₆alkyl such as methyl or ethyl.

In other embodiments, R₃ is alkoxy, for example, C₁₋₆alkoxy such asmethoxy or ethoxy. In some embodiments, the alkoxy is substituted with,for example, one or more halo. One preferred substituted alkoxy isdifluoromethoxy.

In some embodiments, R₃ is hydroxyalkylene, for example,hydroxyC₁₋₆alklene such as —CH₂—OH and —CH₂CH₂—OH. In yet otherembodiments, R₃ is OH.

In other preferred embodiments, R₃ is halo, preferably any one of F, Cl,or Br.

In still other embodiments, R₃ is phenyl. In some embodiments, thephenyl can be substituted with one or more halo, for example, phenylsubstituted with at least one of F, Cl, or Br.

In certain embodiments, R₃ is triazolyl, with 1,2,3-triazolyl beingpreferred. The triazolyl can be attached through any available atom. Inpreferred embodiments, the 1,2,3-triazolyl is attached through the2-position nitrogen atom. In other embodiments, the 1,2,3-triazolyl isattached through the 1-position nitrogen atom.

In yet other embodiments, R₃ is oxazolyl, which can be attached throughany available atom, preferably attached through the 2-position carbon.In some embodiments, the oxazolyl can be substituted with alkyl, forexample, a C₁₋₆alkyl such as methyl.

In other embodiments, R₃ is isoxazolyl, which can be attached throughany available atom. In some embodiments, the isoxazolyl can besubstituted with alkyl, for example, a C₁₋₆alkyl such as methyl.

In other embodiments, R₃ is oxadiazolyl, which can be a1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or1,3,4-oxadiazolyl. Preferably, the oxadiazolyl is 1,2,4-oxadiazolyl. Theoxadiazolyl can be attached through any available atom. In someembodiments, the oxadiazolyl can be substituted with alkyl, for example,C₁₋₆alkyl such as methyl.

In still other embodiments, R₃ is pyridyl, which can be attached throughany available carbon atom. In some embodiments, the pyridyl can besubstituted with one or more alkyl, for example, C₁₋₆alkyl such asmethyl.

In other embodiments, R₃ is pyrazolyl, which can be attached through anyavailable atom. In some embodiments, the pyrazolyl can be substitutedwith one or two alkyl, for example, C₁₋₆alkyl such as methyl.

In certain embodiments, R₃ is pyrimidinyl, which can be attached throughany available carbon atom. In other embodiments, R₃ is pyrazinyl, whichcan be attached through any available carbon atom. In yet otherembodiments, R₃ is pyridazinyl, which can be attached through anyavailable carbon atom.

In other embodiments, R₃ is piperazinyl which can be attached throughany available atom. In some embodiments, one or both nitrogen atoms ofthe piperazinyl may be substituted with H or alkyl, for example,C₁₋₆alkyl such as methyl.

In still other embodiments, R₃ is morpholinyl, which can be attachedthrough any available atom. In some embodiments, the nitrogen atom ofthe morpholinyl may be substituted with H or alkyl, for example,C₁₋₆alkyl such as methyl.

In yet other embodiments, R₃ is pyrrolidinyl, which can be attachedthrough any available atom. In some embodiments, the nitrogen atom ofthe pyrrolidinyl may be substituted with H or alkyl, for example,C₁₋₆alkyl such as methyl.

In other embodiments, R₃ is dialkylamino, for example, dimethylamino,diethylamino, or methylethylamino.

In other embodiments, R₃ is pyrazolyl, which can be attached through anyavailable atom. In some embodiments, the pyrazolyl can be substitutedwith one or two alkyl, for example, C₁₋₆alkyl such as methyl.

In still other embodiments, R₃ is thiophenyl, which can be attachedthrough any available carbon atom.

In preferred embodiments of the invention, R₄ is H. In otherembodiments, R₄ is alkyl, for example, C₁₋₆alkyl such as methyl orethyl. In still other embodiments, R₄ is alkoxy, for example, C₁₋₆alkoxysuch as methoxy or ethoxy. In yet other embodiments, R₄ is halo,preferably, any one of F, Cl, or Br.

In some embodiments, R₃ and R₄, together with the atoms to which theyare attached, form a 6-membered aryl ring.

In other embodiments, R₃ and R₄, together with the atoms to which theyare attached, form a 6-membered heteroarylaryl ring.

In preferred embodiments of the invention, R₅ is a heteroaryl ring.According to some embodiments of the invention, R₅ is pyridyl, which canbe attached through any available atom, optionally substituted with aone or two substituents independently selected from the group consistingof alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl,for example trifluoromethyl.

According to some embodiments of the invention, R₅ is pyrimidinyl, whichcan be attached through any available atom, optionally substituted witha one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is pyrazinyl, whichcan be attached through any available atom, optionally substituted witha one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is pyridazinyl, whichcan be attached through any available atom, optionally substituted witha one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is quinazolinyl,which can be attached through any available atom, optionally substitutedwith a one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is quinoxalinyl,which can be attached through any available atom, optionally substitutedwith a one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is pyrazolyl, whichcan be attached through any available atom, optionally substituted witha one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl. In some embodiments, thepyrazolyl is methyl-pyrazolyl substituted with trifluoromethyl.

According to some embodiments of the invention, R₅ is benzoxazolyl,which can be attached through any available atom, optionally substitutedwith a one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is imidazopyrazinyl,which can be attached through any available atom, optionally substitutedwith a one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is triazolopyrazinyl,which can be attached through any available atom, optionally substitutedwith a one or two substituents independently selected from the groupconsisting of alkyl, alkoxy, or halo. In some embodiments, alkyl istrihaloalkyl, for example trifluoromethyl.

In some embodiments of the invention n is 0. In other embodiments, n is1.

The invention relates to methods of using the compounds described hereinto treat subjects diagnosed with or suffering from a disease, disorder,or condition mediated by orexin receptor activity. These methods areaccomplished by administering to the subject a compound of theinvention.

Diseases, disorders, and conditions mediated by orexin receptor activityinclude disorders of the sleep-wake cycle, insomnia, restless legssyndrome, jet-lag, disturbed sleep, sleep disorders secondary toneurological disorders, mania, depression, manic depression,schizophrenia, pain syndromes, fibromyalgia, neuropathic pain,catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium,dementia, overweight, obesity, or conditions related to overweight orobesity, insulin resistance, type II diabetes, hyperlipidemia,gallstones, angina, hypertension, breathlessness, tachycardia,infertility, sleep apnea, back and joint pain, varicose veins,osteoarthritis, hypertension, tachycardia, arrhythmias, angina pectoris,acute heart failure, ulcers, irritable bowel syndrome, diarrheagastroesophageal reflux, mood disorders, post-traumatic stress disorder,panic disorders, attention deficit disorders, cognitive deficiencies, orsubstance abuse.

Compounds of the invention are particularly suited for the treatment ofmood disorders, post-traumatic stress disorder, panic disorders,attention deficit disorders, cognitive deficiencies, or substance abuse.

Sleep disorders include, but are not limited to, sleep-wake transitiondisorders, insomnia, restless legs syndrome, jet-lag, disturbed sleep,and sleep disorders secondary to neurological disorders (e.g., manias,depressions, manic depression, schizophrenia, and pain syndromes (e.g.,fibromyalgia, neuropathic).

Metabolic disorders include, but are not limited to, overweight orobesity and conditions related to overweight or obesity, such as insulinresistance, type II diabetes, hyperlipidemia, gallstones, angina,hypertension, breathlessness, tachycardia, infertility, sleep apnea,back and joint pain, varicose veins and osteoarthritis.

Neurological disorders include, but are not limited to, Parkinson'sdisease, Alzheimer's disease, Tourette's Syndrome, catatonia, anxiety,delirium and dementias.

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention may be used in combinationwith additional active ingredients in the treatment of the aboveconditions. The additional active ingredients may be coadministeredseparately with a compound of the invention or included with such anagent in a pharmaceutical composition according to the invention. In anexemplary embodiment, additional active ingredients are those that areknown or discovered to be effective in the treatment of conditions,disorders, or diseases mediated by orexin activity, such as anotherorexin modulator or a compound active against another target associatedwith the particular condition, disorder, or disease. The combination mayserve to increase efficacy (e.g., by including in the combination acompound potentiating the potency or effectiveness of an active agentaccording to the invention), decrease one or more side effects, ordecrease the required dose of the active agent according to theinvention.

The compounds of the invention are used, alone or in combination withone or more additional active ingredients, to formulate pharmaceuticalcompositions of the invention. A pharmaceutical composition of theinvention comprises: (a) an effective amount of at least one compound inaccordance with the invention; and (b) a pharmaceutically acceptableexcipient.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily. For example, a total daily dosage of about5 mg to 5 g daily may be accomplished by dosing once, twice, three, orfour times per day.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Intermediate compounds of formula (IIIa) and (IIIb) can be prepared asoutlined in Scheme 1 from commercially available or syntheticallyaccessible compounds of formula (A) where R₃, R₄, X and Y are defined informula (I) as above. Compounds of formula (IIa) and (IIb), are obtainedby reacting a compound of formula (A), with commercially available1,2,3-triazole, in the presence K₂CO₃ in DMF or dioxane, at temperaturesranging from about 60° C. to about 100° C. Compounds of formula (IIIa)and (IIIb) are obtained by reacting compounds of formula (II) in thepresence of a base such as NaOH in a solvent such as EtOH attemperatures ranging from 80° C. to 100° C. One skilled in the art willrecognize that 1,2,3-triazole can exist in two tautomeric forms definedas 2H-[1,2,3]triazole and 1H-[1,2,3]triazole thus accounting for theformation of (IIIa) and (IIIb).

Intermediate compounds of formula (III) can be prepared as outlined inScheme 2 from commercially available or synthetically accessiblecompounds of formula (IVa-c). Compounds of formula (III), (Va) and (Vb)are obtained by reacting compounds of formula (IVa), (IVb) and (IVc)where Hal is —Br, or —I; W is CO₂H, CO₂Alkyl, or CN and R₃ and R₄ are—H, halo, —C₁₋₄alkyl, —C₁₋₄alkoxy and R₃ and R₄ together with the atomsto which they are attached form a 6-membered aryl or 6 memberedheteroaryl ring, with commercially available 1,2,3-triazole, in thepresence of, for example, copper(I)iodide, Cs₂CO₃ andtrans-N,N′-dimethyl-1,2-cyclohexanediamine in, for example, DMF ordioxane, at temperatures ranging from about 60° C. to about 120° C.Compounds of formula (IVc) can be converted to the corresponding esters(Vb) by treatment with, for example, alkyl iodide in the presence of abase such as K₂CO₃ in a solvent such as DMF. Compounds of formula (III)are obtained by reacting a compound of formula (Va) and (Vb) in thepresence of a base such as NaOH in a solvent such as EtOH attemperatures ranging from about 80° C. to about 100° C. One skilled inthe art will recognize that 1,2,3-triazole can exist in two tautomericforms defined as 2H-[1,2,3]triazole and 1H-[1,2,3]triazole thuscompounds of formula (Va), (Vb), and (III) can also exist as the N1linked variant (structure not shown).

Intermediate compounds of formula (IX) are prepared as outlined inScheme 3 from commercially available or synthetically accessiblecompounds of formula (VI) where R₃, R₄, X, and Y are defined as informula I above, G is SnBu₃ or 4,4,5,5 tetramethyl-1,dioxaboralane and Dis Cl, or Br, preferably Br in this case. Compounds of formula (VIII)are obtained by reacting a compound of formula (VI) with commerciallyavailable (VII) in the presence of a catalyst such as1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride and abase such as Na₂CO₃ in a solvent such as 2-MeTHF or THF at temperaturesranging from about 60° C. to about 90° C. Compounds of formula (IX) areobtained by reacting a compound of formula (VIII) in the presence of abase such as NaOH in a solvent such as MeOH at temperatures ranging fromabout 80° C. to about 100° C. or acids such as H₂SO₄ in solvents such asH₂O at temperatures ranging from about 80 to about 100° C.

Intermediate compound (XIV) is prepared as outlined in Scheme 4 fromcommercially available compound (X). Compounds (XI) are obtained byreacting compound (X) with commercially available acrolein in a solventsuch as 1,4 dioxane at temperatures of about 200° C. in a microwavereactor. Compound (XII) can be prepared from compound (XI) by treatmentwith an acid such as HBr in a solvent such as toluene at a temperatureof about 90° C. Compound (XIII) can be obtained by treatment of compound(XII) with commercially available iodoethane and a base such as K₂CO₃ ina solvent such as DMF at temperatures ranging from about 45° C. to about65° C. Compound (XIV) is obtained by treating compound (XIII) with abase such as NaOH in a solvent such as MeOH at temperatures ranging fromabout 80° C. to about 100° C.

Intermediate compounds of formula (XVI) are prepared as outlined inScheme 5 from commercially available or synthetically accessiblecompounds of formula (XIV) where R² is —H, —C₁₋₄alkyl, or —C₁₋₄alkoxyand D is Cl, or Br. Compounds of formula (XV) are obtained by reacting acompound of formula (XIV) with commercially available (VII) in thepresence of a catalyst such as Pd(dppf)Cl₂ and a base such as Na₂CO₃ ina solvent such as 2-MeTHF at temperatures ranging from 75° C. to 150° C.Compounds of formula (XVI) are obtained by reacting a compound offormula (XV) in the presence of a base such as NaOH in a solvent such asMeOH at temperatures ranging from about 80° C. to about 100° C.

Intermediate compounds of formula (XXI) can be prepared as outlined inScheme 6 from commercially available or synthetically accessiblecompounds of formula (XVII) where Hal is Br or I; and where R₃ and R₄are —H, halo, alkyl, alkoxy. Compounds of formula (XVIIIa) can beconverted to the corresponding ester (XVIIIb) by treatment with thionylchloride in a solvent such as MeOH. Compounds of the formula (XX) areobtained by reacting compounds of formula (XVIIIb) with commerciallyavailable compounds of the formula XIX where L is a heterocycle such aspyrazolyl, pyridyl, or oxazolyl; G is SnBu₃ or 4,4,5,5tetramethyl-1,dioxaboralane and R₁ and R₂ are —H, -alkyl, or -alkoxy inthe presence of a catalyst such as Pd(Ph₃P)₄ and a base such as Na₂CO₃in a mixture of solvents such as DME and H₂O at temperatures rangingfrom 100° C. to 150° C. Compounds of formula (XXI) are obtained byreacting a compound of formula (XX) in the presence of a base such asNaOH in a solvent such as MeOH at temperatures ranging from about 80° C.to about 100° C.

Intermediate compounds of formula (XXIV) and (XXVII) are readilyprepared as outlined in Scheme 7 from commercially available orsynthetically accessible compounds of formula (XXII) or (XXV). Compoundsof formula (XXIII) can be obtained from compounds of formula (XXII) asdescribed in the references listed in Scheme 7. Compounds of formula(XXIV) can be obtained from compounds of formula (XXIII) by treatmentwith reducing agents such as Dibal-H, LiAlH₄ or LiBH₄ in solvents suchas THF or diethyl ether at temperatures ranging from about 0° C. toabout 70° C. Compounds of formula (XXVI) can be obtained from compoundsof formula (XXIII) by treatment with bases such as aqueous sodiumhydroxide, potassium hydroxide and lithium hydroxide in solvents such aswater, methanol or THF. Compounds of formula (XXVI) can also be obtainedfrom compounds of formula (XXV) using procedures described in WO2004074292.

Referring to Scheme 8, where PG₁ is a Boc protecting group, compounds offormula (±)-(XXVII) were resolved into individual enantiomers of formula(+)-(XXVII) and (−)-(XXVII) using SFC chromatography on a chiral SFC(CHIRALPAK IC 5 μM 250×20 mm) column using 80% CO₂/20% iPrOH as themobile phase.

Referring to Scheme 9, where PG₁ is a Boc protecting group, compounds offormula (XXVIII) are prepared compounds of formula (+)-(XXIX). Compoundsof formula (XXVIII) are readily prepared from compounds of formula(+)-(XXVII) by treatment with metal catalyst such as PtO₂, Pd/C, orPd(OH)₂ in solvents such as AcOH, MeOH or EtOH under an atmosphere ofhydrogen. Compounds of formula (XXIX) are readily prepared fromcompounds of formula (XXVIII) by reaction with DPPA and TEA in a solventsuch as toluene at temperatures ranging from about 0° C. to about 100°C., preferably about 65° C. for a period of about 1 to 8 hours. BnOH isthen added to afford a compound of formula (XXIX).

According to Scheme 10, compound (XXXI) is obtained by reaction ofcompound (XXX) with, for example, DPPA and TEA in a solvent such astoluene at temperatures ranging from about 0° C. to about 100° C.,preferably about 65° C. for a period of about 1 to 8 hours, preferablyabout 4 h. BnOH is then added to afford a compound of formula (XXXI).Compound (XXXII) is obtained from compound (XXXI) by reaction withtrimethylphenyl ammonium tribromide at temperatures ranging from about0° C. to about 23° C., preferably about 0° C. for a period of from 2 to6 hours, preferably about 4 hours. Compound (XXIII) is obtained fromcompound (XXXII) by treatment with a base, preferably NaH is a solventsuch as DMF. Compound (XXXIV) is obtained from compound (XXXIII) byelimination of HBr with tBuOK in a solvent such as THF in the presencefor a period ranging from 2 to 24 hours. Compound (XXXV) is obtainedfrom compound (XXXIV) by hydroboration oxidation by treating thecompound (XXXIV) with borane in a solvent such as THF at temperaturesranging from about 0° C. to about 23° C., preferably at about 23° C.,for 2 to 12 hours, preferably about 2 hours followed by reaction with,for example, hydrogen peroxide in the presence of a base such as sodiumhydroxide.

Referring to Scheme 11, one skilled in the art would recognize thatcompounds of formula (XLI) may be obtained from compounds of formula(XXXVI) by converging pathways. In one sequence, a compound of formula(XXXVII) is obtained by treating a compound of formula (XXXVI) withR⁵Cl, where R⁵ is optionally substituted pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, quinazolinyl, quinoxalinyl, pyrazolyl, benzoxazolyl,imidazopyrazinyl, triazolopyrazinyl. Commercially available orsynthetically accessible suitably substituted heteroaryl compounds offormula R⁵Cl are reacted with compounds of formula (XXXVI), in thepresence of a suitably selected tertiary organic or inorganic base suchas NaH, Cs₂CO₃, K₂CO₃, TEA, iPr₂NEt and the like; in a solvent such asDMF, dichloromethane, THF, and the like; at a temperature between roomtemperature and the reflux temperature of the solvent. In a preferredembodiment the base is NaH and the solvent is DMF. Removal of thetert-butylcarbamate (Boc) in compounds of formula (XXXVII) isaccomplished by using methods known to one skilled in the art, such as,HCl, TFA, or p-toluenesulfonic acid, in a solvent such as CH₃OH,dioxane, or CH₂Cl₂. In a preferred embodiment, a compound of formula(XXXVII) is treated with TFA in DCM or HCl to afford a compound offormula (XXXVIII). A compound of formula (XLI) is obtained by treating acompound of formula (XXXVIII) with (R¹R²A)CO₂H, where R¹ is H, alkyl,alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl,isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl,pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, ordialkylamino and R₂ is H, alkyl, alkoxy, or halo. Commercially availableor synthetically accessible suitably substituted carboxylic acidcompounds of formula (R¹R²A)CO₂H are combined with compounds of formula(XXXVIII) using under amide coupling methods known to one skilled in theart, such as, CDI, EDCI, HATU, or T3P in a solvent such as THF, DCM, orDMF In a preferred embodiment, a compound of formula (XXXVIII) and(R¹R²A)CO₂H are treated with EDCI in the presence of HOBT in DMF atambient temperature to afford a compound of formula (XLI). One skilledin the art would recognize that compounds of formula (XLI) may also beobtained from compounds of formula (XL). Removal of thetert-butylcarbamate (Boc) in compounds of formula (XXXVI) isaccomplished by using methods known to one skilled in the art, such as,HCl, TFA, or p-toluenesulfonic acid, in a solvent such as CH₃OH,dioxane, or CH₂Cl₂. In a preferred embodiment, a compound of formula(XXXVI) is treated with TFA in DCM or HCl to afford a compound offormula (XXXIX). A compound of formula (XL) is obtained by treating acompound of formula (XXXIX) with (R¹R²A)CO₂H. Commercially available orsynthetically accessible suitably substituted carboxylic acid compoundsof formula (R¹R²A)CO₂H are combined with compounds of formula (XXXIX)using under amide coupling methods known to one skilled in the art, suchas, CDI, EDCI, HATU, or T3P in a solvent such as THF, DCM, or DMF In apreferred embodiment, a compound of formula (XXXIX) and (R¹R²A)CO₂H aretreated with EDCI in the presence of HOBT in DMF at ambient temperatureto afford a compound of formula (XL). A compound of formula (XLI) isobtained by treating a compound of formula (XL) with R⁵Cl. Commerciallyavailable or synthetically accessible suitably substituted heteroarylcompounds of formula R⁵Cl are reacted with compounds of formula (XL), inthe presence of a suitably selected tertiary organic or inorganic basesuch as NaH, Cs₂CO₃, K₂CO₃, TEA, iPr₂NEt and the like; in a solvent suchas DMF, dichloromethane, THF, and the like; at a temperature betweenroom temperature and the reflux temperature of the solvent. In apreferred embodiment the base is NaH and the solvent is DMF to providecompounds of formula (XLI).

Referring to Scheme 12, compounds of formula (XLVI) were synthesizedfrom compounds of formula (XLII) where PG₁ is Boc, PG₃ is Cbz, Z is O orNH and n is 0 or 1. PG₃ was removed when compound of formula (XLII) wastreated with, for example, a Pd catalyst such as 10 wt % Pd/C wetDegussa under an atmosphere of H₂ in a solvent such as EtOH to givecompound of formula (XLIII). Compounds of formula (XLIV) were obtainedfrom compounds of formula (XLIII) using compounds of formula (XLVIII) ina suitable solvent such as DMSO or DMF in the presence of a base such asK₂CO₃ at a temperature of about 70° C. Compounds of formula (XLIV) couldalso be obtained when compounds of formula (XLIII) and (XLVIII) weretreated with a Pd catalyst such as Pd(OAc)₂, a ligand such as racemicBINAP, a base such as sodium tert-butoxide in a solvent such as tolueneat a temperature of about 70° C. Compound of formula (XLV) were obtainedfrom compounds of formula (XLIV) when treated with an acid such as HClin a suitable solvent such as EtOAc or DCM at room temperature. Compoundof formula (XLVI) were obtained from compounds of formula (XLV) usingcompounds of formula (XLVII) in a suitable solvent such as DMF or DCM inthe presence of a peptide coupling reagent such as HATU or T3P, a basesuch as DIPEA at a temperature ranging from room temperature to about45° C.

Referring to Scheme 13, compounds of formula (L) were obtained fromcompound of formula (XLIX) using compounds of formula (LI) in a solventsuch as DME in the presence of a Pd catalyst such as Pd(PPh₃)₄, anadditive or catalyst such as copper iodide at a temperature ranging fromabout 120° C. to about 150° C.

EXAMPLES Abbreviations

Term Acronym Acetic Acid HOAc Acetonitrile ACN Apparent app Aqueous aqAtmosphere atm 2-(1H-9-Azobenzotriazole-1-yl)-1,1,3,3- HATUtetramethylaminium hexafluorophosphate Benzyl Bn2,2′-bis(diphenylphosphino)-1,1′-binaphthalene BINAP [1,1′-Bis(di-tert-PdCl₂(dtbpf) butylphosphino)ferrocene]dichloropalladium(II) Broad brtert-Butylcarbamoyl Boc/Boc Dichloromethane DCM DiisopropylethylamineDIPEA 1,2-Dimethoxyethane DME N,N-Dimethylformamide DMFDimethylsulfoxide DMSO Doublet d Electrospray ionization ESIEnantiomeric excess ee Ethanol EtOH Ethyl Acetate EtOAc, or EA Grams gHertz Hz High-pressure liquid chromatography HPLC Hours h Liquidchromatography and mass spectrometry LCMS Mass spectrometry MS Mass tocharge ratio m/z Methanol MeOH Microliter μL Milligrams mg Milliliter mLMillimoles mmol Minute min Molar M Multiplet m Normal N Nuclear magneticresonance NMR Palladium on carbon Pd/C Palladium hydroxide on carbonPd(OH)₂/C Parts per million ppm Phenyl Ph Propylphosphonic anhydride T₃PRetention time R_(t) Room temperature rt Quartet q Singlet sSupercritical Fluid Chromatography SFC Temperature T Thin layerchromatography TLC Times X Triethylamine TEA Trifluoroacetic acid TFATriplet t

Chemistry:

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄, filtered and concentrated. Where mixtures, solutions, andextracts were “concentrated”, they were typically concentrated on arotary evaporator under reduced pressure. Reactions under microwaveirradiation conditions were carried out in a Biotage Initiator or CEMDiscover instrument.

Melting point determinations were performed in open capillary tubes on aFP62 or MP50 apparatus (Mettler-Toledo). Melting points were measuredwith a temperature gradient of 10° C./minute. Maximum temperature was300° C. The melting point was read from a digital display.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) using prepackaged cartridges, eluting with the indicatedsolvents.

Where compounds were purified by “Prep HPLC” the method employed waseither:

Preparative reverse-phase high performance liquid chromatography (HPLC)was performed on a Gilson HPLC with an Xterra Prep RP₁₈ (5 m, 30×100 mm,or 50×150 mm) column, and a gradient of 10 to 99% acetonitrile/water (20mM NH₄OH) over 12 to 18 min, and a flow rate of 30 mL/min. or

Preparative reverse-phase high performance liquid chromatography (HPLC)was performed on a Agilent 1100 Series HPLC with an XBridge C18 column(5 m, 30×100 mm), mobile phase of 5% ACN in 20 mM NH4OH (hold for 2 min)then ramp 5-99% ACN over 15 min, hold at 99% ACN for 5 min. and a flowrate of 40 mL/min. or

Preparative reverse-phase high performance liquid chromatography (HPLC)was performed on a Agilent 1100 Series HPLC with an XBridge C18 column(5 m, 50×100 mm), mobile phase of 5% ACN in 20 mM NH4OH (hold for 2 min)then ramp 5-99% ACN over 15 min, hold at 99% ACN for 5 min. and a flowrate of 80 mL/min. or

Preparative reverse-phase high performance liquid chromatography (HPLC)was performed on a Gilson HPLC with an Xterra Prep RP₁₈ (5 μm, 30×100mm, or 50×150 mm) column, and a gradient of 10 to 99% acetonitrile/water(20 mM NH₄OH) over 12 to 18 min, and a flow rate of 30 mL/min.

Analytical chromatography data was acquired using an Agilent 1100 HPLC,with an Inertsil ODS-3 3 mm 4.6×50 mm column, purchased from GL Sciences(Part #1010L050W046). Samples were run using a gradient profile of10-99% acetonitrile (ACN) in water, each containing 0.05%trifluoroacetic acid (TFA) over 1.6 minutes, then holding at 99%acetonitrile for 0.3 minutes. Flow rate was 5 mL/min and columntemperature was set to 50° C. (Method A).

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (multiplicity,coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ACD/Name Version 10.01 (Advanced ChemistryDevelopment, Toronto, Ontario, Canada).

Where compounds were purified by “SFC Chromatography” the methodemployed was either:

On preparative APS 1010 system with autoprep otion from Bergerinstrument, consisted of two varian SD-1 pumps (walnut creek, CA, USA),one of which was extensively modified to pump CO₂, a special pump headheat exchanger, ajulabo FT 401 chiller (labortechnik GmbH, Sellback,Germany), a model SCM 2500 phase separator (berger instruments) withselection valve and set of collection vessels in a Bodan robot. A modelKnauer 2500 UV detector with high pressure flow cell (berlin, germany).Sample were applied using a six-port injection valve (Valco, Houston,Tex., USA)) with a 5 ml sample loop and a model YP-300 syringue pump(cavro, san Jose, Calif.). or

On a SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Modifier waspump with a model K1800 Knauer (Berlin, germany), with 100 ml Pump Head.The CO₂ was pump with 2 lewa pumps (Leonberg Germany). Cooling of thepump head and the CO2 line was achieved by a coil alimented by a Huberchiller (Offenburg/Germany). Sample injections were made using 6switching valves (Valco, Houston, Tex., USA) and a 5 ml sample loop. Thesystem is managed by a PLC automation system.

Intermediates

Intermediate Name Structure Reference A-1 2-(2H-1,2,3-trizol-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 2. A-23-fluoro-2-(pyrimidin- 2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 50. A-36-methyl-2-(2H- 1,2,3-triazol-2- yl)nicotinic acid

Prepared according to WO 2011/050198 Intermediate70 A-4 6-methyl-2-(2H-1,2,3-triazol-1- yl)nicotinic acid

Prepared according to WO 2011/050198 Intermediate 71 A-54-methoxy-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 54 A-6 2-fluoro-6-(pyrimidin-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 14. A-7 5-fluoro-2-(pyrimidin-2- yl)benzoic acid.

Prepared according to WO 2011/050198 Intermediate 13. A-8 3-ethoxy-6-methylpicolinic acid

WO 2010/063663 Description 39 A-9 6-methyl-3- (pyrimidin-2- yl)picolinicacid

WO 2010/063663 Description 69 A-10 5-fluoro-2-(2H- 1,2,3-triazol-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 1. A-112-fluoro-6-(2H- 1,2.3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 12. A-124-fluoro-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 4. A-132-methoxy-6-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared analogous to Intermediate A-X using 2-bromo-6-(2H-1,2,3-triazol- 2-yl)benzoic acid A-14 2-methyl-6-(2H-1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 82. A-15 4-methoxy-2-(pyrimidin-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 88. A-163-fluoro-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 5. A-17 3-fluoro-2-(3-methyl-1,2,4- oxadiazol-5- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 63. A-185-methoxy-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 10

Synthesis of 3-fluoro-2-(pyrimidin-2-yl)benzonitrile (Intermediate inthe synthesis of intermediate A-2)

To a solution of3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(4.98 g, 19.1 mmol) and 2-bromopyridine (3.85 g, 23 mmol) in THF (96 mL)was added Na₂CO₃ (6 g, 57.4 mmol) followed by water (43 mL). Thereaction mixture was degassed with N₂ for 10 minutes. PdCl₂(dtbpf) (374mg, 0.57 mmol) was added and the reaction mixture was stirred at 80° C.for 5 h. The solution was cooled to room temperature and a mixture ofEtOAc and water was added. The aqueous was extracted twice with EtOAcand the combined organic layers were dried over MgSO4, filtered andevaporated. The title compound was precipitated by dissolving theresidue in a minimum amount of EtOAc and then adding hexanes. The solidwas filtered, washed with hexanes and dried to afford the title compound(2.46 g, 64%). MS (ESI) mass calcd. for C₁₁H₆FN₃, 199.1; m/z found 200.1[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 9.02-8.91 (m, 2H), 7.65 (dt,J=7.7, 1.0 Hz, 1H), 7.60-7.52 (m, 1H), 7.51-7.43 (m, 1H), 7.41 (t, J=4.9Hz, 1H).

Intermediate A-19: 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step A: 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile. To3-bromo-5-methylpicolinonitrile (1.5 g, 7.6 mmol) in DMF (19 mL) wasadded K₂CO₃ (1.2 g, 8.4 mmol) and 2H-1,2,3-triazole (440 μL, 7.6 mmol).The mixture was heated to 100° C. for 16 h, cooled to rt and extractedwith EtOAc (2×). The combined organics were dried (Na₂SO₄) andconcentrated. Purification via silica gel chromatography (5-60% EtOAc inhexanes) gave the title compound (490 mg, 35%) ¹H NMR (500 MHz, CDCl₃)8.58-8.53 (m, 1H), 8.29-8.24 (m, 1H), 7.98 (s, 2H), 2.54 (s, 3H) and5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinonitrile (387 mg, 27%).

Step B: 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinate. To a solution ofthe title compound of Step A (489 mg, 2.6 mmol) in EtOH (7 mL) was added4 N NaOH (660 μL, 2.6 mmol). The mixture was heated at 100° C. for 24 h.The reaction mixture was concentrated in vacuo to a white solid whichwas used without further purification in subsequent steps. MS (ESI) masscalcd. for C₉H₈N₄O₂, 204.1; m/z found 205.0 [M+H]⁺.

Intermediate A-20: 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinic acid

Step A: 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinonitrile. The titlecompound was prepared in Intermediate A-19 Step A. ¹H NMR (500 MHz,CDCl₃) 8.65 (dd, J=1.8, 0.9 Hz, 1H), 8.41 (d, J=1.2 Hz, 1H), 8.18-8.15(m, 1H), 7.95 (d, J=1.2 Hz, 1H), 2.58 (s, 3H).

Step B: 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinic acid. Preparedanalogous to Intermediate A-19 substituting5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile with the titlecompound of Step A. MS (ESI) mass calcd. for C₉H₈N₄O₂, 204.1; m/z found205.0 [M+H]⁺.

Intermediate A-21: 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step A: 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile. To3-bromo-5-methylpicolinonitrile (2.2 g, 11 mmol) in DMF (28 mL) wasadded K₂CO₃ (1.7 g, 12 mmol) and 2H-1,2,3-triazole (650 μL, 11 mmol).The mixture was heated to 100° C. for 36 h, cooled to rt and extractedwith EtOAc. The combined organics were dried (Na₂SO₄) and concentrated.Purification via silica gel chromatography (10-100% EtOAc in hexanes)gave the title compound (1 g, 48%).

Step B: 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. To a solutionof the title compound of Step A (730 mg, 4 mmol) in EtOH (10 mL) wasadded 4 N NaOH (1 mL, 4 mmol). The mixture was heated at 100° C. for 24h. The reaction mixture was concentrated in vacuo to a white solid whichwas used without further purification in subsequent steps.

Intermediate A-22: 3-ethoxyisoquinoline-4-carboxylic acid

Step A: ethyl 3-hydroxyisoquinoline-4-carboxylate. To a suspension ofethyl 3-aminoisoquinoline-4-carboxylate (583 mg, 2.70 mmol) in 6.8 mL ofH₂SO₄ 5N cooled to 0° C. was added sodium nitrite (223 mg, 3.24 mmol,dissolved in 1 mL of water). The reaction mixture was stirred at 0° C.for 2.5 h and then NaOH_((aq)) 1N was added until pH=7. The aqueousphase was extracted twice with DCM and the combined organic phases weredried over MgSO₄, filtered and evaporated to give the title compound ofStep A which was used without further purification in the next step (583mg, 99%). MS (ESI) mass calcd. for C₁₂H₁₁NO₃, 217.1; m/z found 218.1[M+H]⁺.

Step B: ethyl 3-ethoxyisoquinoline-4-carboxylate. To the title compoundof Step A (583 mg, 2.68 mmol) in THF (13 mL) was addedtriphenylphosphine (1.06 g, 4.03 mmol), ethanol (0.24 mL, 4.03 mmol) andDIAD (0.79 mL, 4.03 mmol). The reaction mixture was stirred at roomtemperature for 16 h and then the solvent was evaporated. The crude waspurified via silica gel chromatography (0-30% EtOAc in hexanes) toafford the title compound of Step B (498 mg, 76%). MS (ESI) mass calcd.for C₁₄H₁₅NO₃, 245.1; m/z found 246.1 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 8.97 (s, 1H), 7.91-7.82 (m, 2H), 7.65-7.60 (m, 1H),7.42-7.36 (m, 1H), 4.59-4.48 (m, 4H), 1.48-1.39 (m, 6H).

Step C: 3-ethoxyisoquinoline-4-carboxylic acid. The title compound ofStep B (492 mg, 2 mmol) dissolved in MeOH (15 mL) was added NaOH_((aq))2M (2.5 mL). The reaction mixture was stirred at 60° C. for 16 h andthen NaOH_((aq)) 4M (2 mL) was added and the mixture was stirred at 70°C. for 4 h. MeOH was evaporated and the aqueous phase was cooled to 0°C. and acidified with the addition of HCl_((aq)) 6N. The solid wasfiltered, washed with cold water and dried to afford the title compound(285 mg, 65%). MS (ESI) mass calcd. for C₁₂H₁₁NO₃, 217.1; m/z found218.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.15 (s, 1H),8.13-8.06 (m, 1H), 7.82-7.70 (m, 2H), 7.54-7.47 (m, 1H), 4.50 (q, J=7.0Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).

Intermediate A-23: 4-(difluoromethoxy)-2-(2H-1,2,3-triazol-2-yl)benzoicacid

Prepared analogous to Intermediate A-19 substituting2-bromo-6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine with4-(difluoromethoxy)-2-fluorobenzonitrile.

Intermediate Name Structure Reference A-24 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 82 A-254-fluoro-2-(pyrimidin-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 87

Intermediate A-26: 3-methyl-2-(pyrimidin-2-yl)benzoic acid

Step A: methyl 3-methyl-2-(pyrimidin-2-yl)benzoate. In a microwave vialwas dissolved methyl3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (619mg, 2.24 mmol) and 2-chloropyrimidine (314 mg, 2.69 mmol) in 2-MeTHF (10mL). Na₂CO₃ (713 mg, 6.73 mmol) was then added followed by water (3.4mL) and the reaction mixture was degassed with N₂ for 45 minutes.Pd(dppf)Cl₂ (66 mg, 0.09 mmol) and the reaction mixture was heated at75° C. for 28 h. More Pd(dppf)Cl₂ (33 mg, 0.045 mmol) was added and thereaction mixture was heated at 150° C. for 3.5 h. The mixture wasfiltered through a pad of celite and rinsed with EtOAc and water. Thelayers were separated and the aqueous was extracted once with EtOAc. Thecombined organic layers were dried over MgSO₄, filtered and evaporated.The crude was purified via silica gel chromatography (0-50% EtOAc inhexanes) to afford the title compound (116 mg, 23%). MS (ESI) masscalcd. for C₁₃H₁₂N₂O₂, 228.1; m/z found 229.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl3) 8.95-8.76 (m, 2H), 7.99-7.75 (m, 1H), 7.50-7.44 (m, 1H),7.43-7.37 (m, 1H), 7.32-7.24 (m, 1H), 3.64 (s, 3H), 2.15 (s, 3H).

Step B: 3-methyl-2-(pyrimidin-2-yl)benzoic acid. Prepared analogous tointermediate A-31 step B to give title compound. MS (ESI) mass calcd.for C₁₂H₁₀N₂O₂, 214.1; m/z found 215.1 [M+H]⁺.

Intermediate Name Structure Reference A-27 3-(2H-1,2,3- triazol-2-yl)picolinic acid

Prepared according to WO 2011/050198 Intermediate 72

Intermediate A-28: 2-methoxy-6-(pyrimidin-2-yl)benzoic acid

Step A: Methyl 2-methoxy-6-(pyrimidin-2-yl)benzoate. In a microwave vialwas dissolved methyl2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (500mg, 1.71 mmol), commercially available from Combi-Blocks (CAS#1146214-77-8), and 2-bromopyrimidine (344 mg, 2.05 mmol) in THF (8.5mL). Na₂CO₃ (544 mg, 5.14 mmol) was then added followed by water (4 mL)and the reaction mixture was degassed with N₂ for 10 minutes.PdCl₂(dtbpf) (45 mg, 0.069 mmol) was then added and the reaction mixturewas heated at 80° C. for 4 h. The mixture was cooled to room temperatureand water and EtOAc added. The reaction mixture was extracted with EtOAc(3×). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The crude was purified via silica gel chromatography(0-70% EtOAc in hexanes) to afford the title compound (265 mg, 63%). MS(ESI) mass calcd. for C₁₃H₁₂N₂O₃, 244.1; m/z found 245.1 [M+H]⁺. ¹H NMR(400 MHz, Chloroform-d) 8.78 (d, J=4.9 Hz, 2H), 7.99 (dd, J=7.9, 0.9 Hz,1H), 7.49 (t, J=8.1 Hz, 1H), 7.19 (t, J=4.8 Hz, 1H), 7.09 (dd, J=8.3,0.9 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H).

Step B: 2-methoxy-6-(pyrimidin-2-yl)benzoic acid. To a solution of thetitle compound of Step A (265 mg, 1.09 mmol) in THF (4 mL) was added 2 NNaOH (2 mL). The mixture was heated at 50° C. for 72 h. The reactionmixture was concentrated in vacuo to a white solid which was usedwithout further purification in subsequent steps. MS (ESI) mass calcd.for C₁₂H₁₀N₂O₃, 230.1; m/z found 231.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)12.63 (s, 1H), 8.86 (d, J=4.9 Hz, 2H), 7.77 (dd, J=7.9, 1.0 Hz, 1H),7.51 (t, J=8.1 Hz, 1H), 7.45 (t, J=4.9 Hz, 1H), 7.25 (dd, J=8.4, 1.0 Hz,1H), 3.83 (s, 3H).

Intermediate A-29: 7-ethoxyquinoline-8-carboxylic acid

Step A: 7-methoxyquinoline-8-carboxylic acid. In 1 g separate batches amixture of 2-amino-6methoxybenzoic acid (11 g, 66 mmol) and acrolein(4.8 mL, 72 mmol) in 1,4-dioxane (66 mL) was heated in a microwavereactor for 20 min at 200° C. After combining the reactions, the mixturewas concentrated and purified via silica gel chromatography (0-10% MeOHin DCM) to give the title compound (2.8 g, 20%). MS (ESI) mass calcd.for C₁₁H₁₉NO₃, 203.1; m/z found 204.0 [M+H]⁺.

Step B: 7-hydroxyquinoline-8-carboxylic acid. The title compound of StepA (2.9 g, 14.1 mmol) in HBr (14 mL) was heated at 90° C. for 1 h. Themixture was then concentrated washed with PhCH3 and used without furtherpurification in subsequent steps.

Step C: ethyl 7-ethoxyquinoline-8-carboxylate. To the title compound ofStep B (800 mg, 3.9 mmol) and K₂CO₃ (1.4 g, 10.4 mmol) in DMF (15 mL)was added iodoethane (560 μL, 6.9 mmol). After stirring overnight at rt,the reaction was concentrated and purified via silica gel chromatography(0-30% EtOAc in hexanes) to give the title compound. MS (ESI) masscalcd. for C₁₄H₁₅NO₃, 245.1; m/z found 246.0 [M+H]⁺.

Step D: 7-ethoxyquinoline-8-carboxylic acid. To the title compound ofStep C (1.3 g, 5.4 mmol) in THF (22 mL) and H₂O (11 mL) was added LiOHhydrate (675 mg, 16.5 mmol) and MeOH. The mixture was heated at 67° C.for 12 h. Additional LiOH hydrate (675 mg, 16.5 mmol) was added and theheating was continued at 70° C. for 1 days. Additional LiOH hydrate (1.4g, 33 mmol) was added and the heating was continued at 75° C. for 1 day.The reaction was allowed to cool to rt, acidified to pH=3 with 1N HCl(aq) and concentrated. Purification via prep HPLC gave the titlecompound (1 g, 84%). MS (ESI) mass calcd. for C₁₂H₁₁NO₃, 217.1; m/zfound 218.0 [M+H]⁺.

Intermediate A-30: 2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxybenzoicacid

Step A: Ethyl 2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxybenzoate. In amicrowave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg,1.54 mmol) and1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(377 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na₂CO₃ (259 mg,3.09 mmol) was then added followed by Pd(PPh₃)₄ (89 mg, 0.077 mmol) andthe reaction mixture was degassed with N₂ for 10 minutes. The reactionmixture was then heated at 100° C. for 1 h in the microwave. The mixturewas cooled to room temperature, filtered through Celite and washed withEtOAc and DCM. The crude solution was concentrated in vacuo and directlypurified via silica gel chromatography (10-80% EtOAc in hexanes) toafford the title compound (402 mg, 95%). MS (ESI) mass calcd. forC₁₅H₁₈N₂O₃, 274.1; m/z found 275.2 [M+H]⁺. 1H NMR (400 MHz,Chloroform-d) 7.45 (dd, J=8.4, 7.6 Hz, 1H), 7.29 (s, 1H), 7.04 (dd,J=8.5, 0.9 Hz, 1H), 6.84 (dd, J=7.6, 0.9 Hz, 1H), 4.07 (qd, J=7.2, 1.5Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 1.86 (s, 3H), 1.01 (t, J=7.1 Hz,3H).

Step B: 2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxybenzoic acid. Preparedanalogous to intermediate A-28 step B to give title compound. MS (ESI)mass calcd. for C₁₃H₁₄N₂O₃, 246.1; m/z found 247.2 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) 7.50 (dd, J=8.5, 7.6 Hz, 1H), 7.25 (s, 1H), 7.21 (dd,J=8.5, 0.9 Hz, 1H), 6.85 (dd, J=7.6, 0.9 Hz, 1H), 3.84 (s, 3H), 3.49 (s,3H), 1.79 (s, 3H).

Intermediate A-31: 3-methyl-2-(oxazol-2-yl)benzoic acid

Step A: ethyl 3-methyl-2-(oxazol-2-yl)benzoate. In a microwave vial wasdissolved ethyl 2-iodo-3-methylbenzoate (627 mg, 2.16 mmol) and2-(tributylstannyl)oxazole (0.54 mL, 0.07 mmol) in DME (2.59 mL). Thesolution was degassed with N₂ for 5 minutes then CuI (21 mg, 0.11 mmol)and Pd(PPh₃)₄ (125 mg, 0.11 mmol) were added. The reaction was purgedwith N₂ and heated at 150° C. for 1 h. The reaction was cooled to rt,filtered through a pad of celite and purified via silica gelchromatography (0-40% EtOAc in hexanes) to give the title compound ofstep A (333 mg, 67%). MS (ESI) mass calcd. for C₁₃H₁₃NO₃, 231.1; m/zfound 232.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 7.89-7.82 (m, 1H),7.79 (d, J=0.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.30 (d, J=0.9 Hz, 1H), 4.17(q, J=7.1 Hz, 2H), 2.27 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).

Step B: 3-methyl-2-(oxazol-2-yl)benzoic acid. To the title compound ofstep A (166 mg, 0.72 mmol) was added MeOH (7.2 mL) and 1M NaOH_((aq))(7.2 mL). MeOH was evaporated and then 1 M HCl_((aq)) was added. To thesolution was added DCM and the aqueous was extracted with DCM (3×). Thecombined organic layers were dried over MgSO₄, filtered and evaporatedto give the title compound (145 mg). MS (ESI) mass calcd. for C₁₁H₉NO₃,203.1; m/z found 204.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H),7.79-7.68 (m, 1H), 7.65-7.49 (m, 2H), 7.35 (s, 1H), 4.34 (s, 1H), 2.20(s, 3H).

Intermediate A-32: 4-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step A: 4-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile. In amicrowave vial was dissolved 2H-1,2,3-triazole (0.22 mL, 3.8 mmol) andCuI (26 mg) in DMF (4 mL). The reaction mixture was degassed with N₂ and3-bromo-4-methylpicolonitrile (300 mg, 1.5 mmol) was added followed bytrans-N,N′-dimethyl-1,2-cyclohexanediamine (41 μL, 0.3 mmol) and Cs₂CO₃(844 mg, 2.6 mmol). The reaction mixture was heated at 120° C. for 1 hin a microwave reactor. Then H₂O was added and the mixture extractedwith EtOAc. The combined organic layers were dried (MgSO₄). Purificationvia silica gel chromatography (0-50% EtOAc in heptane) gave the titlecompound (112 mg, 27%). MS (ESI) mass calcd. for C₉H₇N₅, 185.2; m/zfound 186 [M+H]⁺.

Step B: 4-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Preparedanalogous to Intermediate A-19 substituting5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile with the titlecompound of Step A. The reaction mixture was acidified to pH=4 beforeconcentrating. MS (ESI) mass calcd. for C₁₁H₉NO₃, 203.1; m/z found 204.1[M+H]⁺.

Intermediate A-33: 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylic acid

Step A: ethyl 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylate. Preparedanalogous to Intermediate A-40 Step A substituting2-bromo-4-methylbenzoic acid with ethyl 3-iodoquinoline-2-carboxylate(WO 2011093365) in <10% yield. MS (ESI) mass calcd. for C₁₄H₁₂N₄O₂,268.3; m/z found 269.0 [M+H]⁺.

Step B: 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylic acid. To thetitle compound of Step A (134 mg, 0.5 mmol) in MeOH (1 mL) was addedaqueous 2M NaOH (1 mL). After 1 h at rt, the reaction was heated to 50°C. for 1 h, cooled to rt, acidified with 1N HCl, concentrated and usedin subsequent steps without further purification. MS (ESI) mass calcd.for C₁₂H₈N₄O₂, 240.2; m/z found 241.0 [M+H]⁺.

Intermediate Name Structure Reference A-34 5-methyl-2- (pyrimidin-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 50. A-35 2-methyl-6-(pyrimidin-2- yl)benzoic acid

Prepared according to intermediate A-34 or A-2 A-36 4-methyl-2-(pyrimidin-2- yl)benzoic acid

Prepared according to intermediate A-34 or A-2 A-375-methyl-2-(2H-1,2,3- triazol-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 8. A-385-chloro-2-(2H-1,2,3- triazol-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 9. A-395-fluoro-2-(1H- pyrazol-5-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 51.

Intermediate A-40: 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

Step A: 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and4-methyl-2-(1H-1,2,3-triazol-1-yl)benzoic acid. In a microwave vial wasdissolved 2H-1,2,3-triazole (0.34 mL, 5.81 mmol) and CuI (40 mg, 0.21mmol) in DMF (5 mL). The reaction mixture was degassed with N₂ for 10minutes and 2-bromo-4-methylbenzoic acid (500 mg, 2.33 mmol) was addedfollowed by trans-N,N′-dimethyl-1,2-cyclohexanediamine (62 μL, 0.40mmol) and Cs₂CO₃ (1.29 g, 3.95 mmol). The reaction mixture was stirredat 100° C. for 20 minutes using a microwave oven before beingpartitioned between water, HCl_((aq)) (pH=3) and EtOAc. The organiclayer was dried over MgSO₄, filtered and evaporated to give the crudeproduct mixture which was used in the next step without any furtherpurification.

Step B: methyl 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoate. To the titlecompound of step A (945 mg, 4.65 mmol) in DMF (28 mL) was added K2CO3(1.3 g, 9.3 mmol) and iodomethane (0.3 mL, 4.7 mmol). The reactionmixture was stirred at room temperature for 16 h under N₂. The solventwas evaporated and the residue was dissolved with a saturated solutionof NaHCO₃. The aqueous phase was extracted with DCM and the organiclayer was dried over MgSO4, filtered and evaporated. The crude materialwas purified via silica gel chromatography (0% to 30% EtOAc/heptane) toafford the title compound (470 mg, 47%).

Step C: Prepared analogous to Intermediate A-31 step B substitutingethyl 3-methyl-2-(oxazol-2-yl)benzoate with the title compound of Step Band used without further purification in subsequent steps.

Intermediate Name Structure Reference A-41 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid

Prepared analogous to intermediate A-17

Intermediate A-42: 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid

Step A: 3-bromo-6-methylpicolinic acid. To3-bromo-6-methylpicolinonitrile (4 g, 20.3 mmol) in EtOH (40 mL) in asealed tube was added aqueous 4M NaOH (15 mL). The reaction was heatedat 90° C. for 24 h. Additional aqueous 4M NaOH was added and heatingcontinued at 90° C. for 24 h. The reaction was cooled to rt, acidifiedto pH=3 with 1N HCl (aq), concentrated and used without furtherpurification in subsequent steps. MS (ESI) mass calcd. for C₇H₆BrNO₂,216.0; m/z found 218 [M+H]⁺.

Step B: Methyl 3-bromo-6-methylpicolinate. To the title compound of stepA (10.3 g, 20 mmol) in MeOH (50 mL) was added thionyl chloride (4.4 mL,60 mmol). The reaction was heated at reflux overnight, cooled to rt andconcentrated. Purification via silica gel chromatography (0-15% EtOAc inheptane) gave the title compound (1.9 g, 40%). MS (ESI) mass calcd. forC₈H₈BrNO₂, 230.1; m/z found 232 [M+H]⁺.

Step C: 3-methyl-2-(tributylstannyl)pyridine. To2-bromo-3-methylpyridine (1.3 mL, 11.7 mmol) in THF (35 mL) at −78° C.was added n-BuLi (2.5 M in hexanes, 5.6 mL, 14 mmol). After 30 min,tri-n-butyltin chloride (3.8 mL, 14 mmol) was added. After 1 h at −78°C., the reaction was allowed to warm to rt. EtOAc was added and thereaction mixture was washed with 10% aq KF. The organic layer was dried(MgSO₄). Purification via silica gel chromatography (0-15% EtOAc inheptane) gave the title compound (1.2 g, 27%). MS (ESI) mass calcd. forC₁₈H₃₃NSn, 382.2; m/z found 384.0 [M+H]⁺.

Step D: methyl 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylate. To thetitle compound of step B (509 mg, 2.2 mmol) and the title compound ofstep C (1.1 g, 2.9 mmol) in PhCH3 (6.6 mL) was added Pd(PPh₃)₄ (225 mg,0.2 mmol). The reaction was degassed with N₂ and heated at 150° C. for1.5 h using microwave reactor. The reaction was cooled to rt, dilutedwith H2O and extracted with EtOAc. The organic layer was dried (MgSO₄).Purification via silica gel chromatography (0-100% EtOAc in heptane)gave the title compound (101 mg, 18%). MS (ESI) mass calcd. forC₁₄H₁₄N₂O₂, 242.3; m/z found 243 [M+H]⁺.

Step E: 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid. Preparedanalogous to intermediate A-33 step B substituting ethyl3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylate with the title compoundof step D. MS (ESI) mass calcd. for C₁₃H₁₂N₂O₂, 228.2; m/z found 229[M+H]⁺.

Intermediate A-43: 6-methyl-3-(oxazol-2-yl)picolinic acid

Prepared analogous to Intermediate A-31 substituting ethyl2-iodo-3-methylbenzoate with methyl 3-iodo-6-methylpicolinate. MS (ESI)mass calcd. for C₁₀H₈N₂O₃, 204.2; m/z found 161 [M-CO2]⁺.

Intermediate Name Structure Reference A-44 6-methyl-3-(3- methyl-1,2,4-oxadiazol-5- yl)picolinic acid

WO 2010/063663 Description 64 A-45 6-methyl-3-(3- methyl-1H-pyrazol-1-yl)picolinic acid

WO 2010/063663 Description 71 A-46 6-methyl-3-(4- methyl-1H-pyrazol-1-yl)picolinic acid

WO 2010/063663 A-47 6-methyl-3-(1H- pyrazol-1- yl)picolinic acid

WO 2010/063663 Description 73 A-48 6-methyl-3-(3- methylisoxazol-5-yl)picolinic acid

WO 2010/063663 Description 117 A-49 1-methyl-3-phenyl- 1H-pyrazole-4-carboxylic acid

Purchased A-50 1-methyl-4-phenyl- 1H-pyrazole-5- carboxylic acid

Purchased A-51 1-methyl-5-phenyl- 1H-pyrazole-5- carboxylic acid

Purchased A-52 5-chloro-3-(2H- 1,2,3-triazol-2- yl)picolinic acid

WO 2012/145581 Intermediate 105 A-53 5-methoxy-3-(2H- 1,2,3-triazol-2-yl)picolinic acid

WO 2012/145581 Intermediate 105 A-54 6-methyl-3-(4- methyloxazol-2-yl)picolinic acid

Intermediate B-1:(±)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid

Prepared as described in as in WO 2004/074 292 A1. ¹H NMR (CDCl3): 4.54(d, J=4.6 Hz, 1H), 4.33-4.24 (m, 1H), 2.61-2.18 (m, 4H), 1.90-1.71 (m,2H), 1.68-1.57 (m, 1H), 1.56-1.35 (m, 10H).

Intermediates (+)-B-2 and (−)-B-2: (1S,2R,4R)-2-benzyl 7-tert-butyl7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate

and (1R,2S,4S)-2-benzyl7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate

The title compounds were obtained by chiral SFC (CHIRALPAK IC 5 μM250×20 mm) resolution of Intermediate B-3 (17 g) using 80% CO₂/20% iPrOHas the mobile phase to give (−)-B-3 enantiomer A (7.5 g, 1st elutingenantiomer) and enantiomer (+)-B3 (7.3 g, 2^(nd) eluting enantiomer).

Intermediate (−)-B-2: (−)-2-benzyl7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate. Enantiomer A,[α]^(D) ₂₅ −25.2 (c 2.8, CHCl₃).

Intermediate (+)-B-2: (+)-2-benzyl7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate. Enantiomer B,[α]^(D) ₂₅ +25.0 (c 2.8, CHCl₃). ¹H NMR (CDCl₃): 7.39-7.30 (m, 5H),5.19-5.08 (m, 2H), 4.55 (s, 1H), 4.30 (s, 1H), 2.59 (dd, J=8.9, 5.0 Hz,1H), 2.36-2.24 (m, 1H), 1.90-1.70 (m, 2H), 1.68-1.57 (m, 1H), 1.52-1.34(m, 11H).

Intermediate B-3:(1S,2R,4R)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylicacid

To intermediate (+)-B-2 (3.5 g, 10.6 mmol) in EtOH (100 mL) was added 10wt % Pd/C wet Degussa (750 mg). The reaction was purged with N₂ followedby H₂, then allowed to proceed under an atmosphere of H₂ (balloon). Uponcompletion, the reaction was filtered and concentrated to give the titlecompound (2.4 g, 94%) that was used without further purification. ¹H NMR(CDCl₃): 4.62-4.52 (m, 1H), 4.35-4.26 (m, 1H), 2.59 (ddd, J=8.9, 5.0,1.5 Hz, 1H), 2.29-2.19 (m, 1H), 1.91-1.71 (m, 2H), 1.68-1.58 (m, 1H),1.54-1.35 (m, 11H).

Intermediate B-4: (1S,2R,4R)-tert-butyl2-(((benzyloxy)carbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate

To intermediate B-3 (2.4 g, 9.9 mmol) in PhCH₃ (32 mL) was added TEA(1.5 mL, 10.9 mmol). After heating in an oil bath to 70° C., DPPA (2.4mL, 10.9 mmol) in PhCH₃ (3 mL) was added. After 1 h, BnOH (1.0 g, 9.5mmol) was added and the oil bath temperature increased to 90° C. Afteran additional 18 h, the reaction was cooled to rt, diluted with EtOAcand washed with saturated NaHCO₃ (aq). The aqueous layer was extractedwith EtOAc (1×). The combined organics were washed with brine and dried(Na₂SO₄). Purification via silica gel chromatography (10-50% EtOAc inhexanes) gave the title compound (2.8 g, 78%). ¹H NMR (CDCl₃): 7.39-7.28(m, 5H), 5.20-4.84 (m, 3H), 4.30-4.06 (m, 3H), 3.86-3.68 (m, 1H), 1.93(dd, J=13.4, 8.1 Hz, 1H), 1.85-1.63 (m, 2H), 1.54-1.29 (m, 11H).

Intermediate B-5: (+)-(1S,2R,4R)-tert-butyl2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate

To intermediate B-4 (400 mg, 1.2 mmol) in EtOH (5 mL) was added 10 wt %Pd/C wet Degussa (85 mg). The reaction was purged with N₂ followed byH₂, then allowed to proceed under an atmosphere of H₂ (balloon). Uponcompletion, the reaction was filtered and concentrated to give the titlecompound (244 mg, 99%) that was used without further purification. MS(ESI) mass calcd. for C₁₁H₂₀N₂O₂, 212.1; m/z found 213.1 [M+H]⁺. [α]^(D)₂₅ +9.8 (c 4.9, CHCl₃) ¹H NMR (CDCl3): 4.25-4.13 (m, 1H), 3.94-3.82 (m,1H), 2.96 (dd, J=7.8, 3.0 Hz. 1H), 1.85-1.25 (m, 15H).

Intermediate B-6: (±)-tert-butyl2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate

Prepared analogous to intermediate B-5 substituting intermediate B-4with (±)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylicacid (intermediate B-1).

Intermediate B-7: (±)-tert-butyl2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate

Intermediate B-8: (−)-(1R,2S,4S)-tert-butyl2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate

Prepared analogous to intermediate B-5 substituting enantiomer(1S,2R,4R)-2-benzyl 7-tert-butyl7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (intermediate (+)-B-2) withenantiomer (1R,2S,4S)-2-benzyl7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (intermediate(−)-B-2).

Intermediate B-9: (1S,2R,4R)-tert-butyl2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

To intermediate (+)-B-2 (504 mg, 1.5 mmol) in THF (12 mL) at 0° C. wasadded Dibal-H (1M in THF, 4.6 mL). After 1 h, additional Dibal-H wasadded. The reaction allowed to warm to rt and quenched with Rochelle'sSalt (20 wt %). EtOAc was added and the mixture allowed to stir until 2clear layers had formed. The aqueous layer was extracted with EtOAc(2×). The combined organics were washed with brine and dried (Na₂SO₄).Purification via silica gel chromatography (10-50% EtOAc in hexanes)gave the title compound (171 mg, 49%). MS (ESI) mass calcd. forC₁₂H₂₁NO₃, 227.2; m/z found 228.2 [M+H]⁺, 172.2 [M−55]⁺. ¹H NMR (CDCl3):4.26-4.12 (m, 2H), 3.45-3.32 (m, 2H), 3.00-2.04 (m, 1H). 1.95-1.90 (m,1H), 1.83-1.73 (m, 2H), 1.53-1.37 (m, 12H), 1.32-1.28 (m, 1H).

Intermediate B-10: (±)-tert-butyl2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

As in Org. Syn., 1997, 74, 212, Tet. Lett. 1997, 38, 6829 and Biorg.Med. Chem. Lett. 2006, 14, 8219 ¹H NMR (CDCl₃): 4.25-4.13 (m, 2H),3.47-3.32 (m, 2H), 1.98-1.68 (m, 4H), 1.56-1.26 (m, 13H).

Example 1(5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Tointermediate B-9 (170 mg, 0.75 mmol) in DMF (3 mL) at 0° C. was addedNaH (36 mg, 60 wt % in mineral oil, 0.9 mmol). After 30 min,2-fluoropyridine (102 mg, 1.0 mmol) in DMF (0.5 mL) was added dropwiseand the 0° C. ice bath was removed. The flask was then heated to 90° C.in an oil bath. After 2 h, ½ saturated NH₄Cl was added and the reactionextracted with EtOAc (2×). The combined organics were washed with brineand dried (Na₂SO₄). Purification via silica gel chromatography (5-30%EtOAc in hexanes) gave the title compound (172 mg, 76%) as a whitesolid. MS (ESI) mass calcd. for C₁₇H₂₄N₂O₃, 304.2; m/z found 305.1[M+H]⁺. ¹H NMR (CDCl₃): 8.13 (dd, J=5.1, 2.0 Hz, 1H), 7.55 (ddd, J=8.7,7.1, 2.0 Hz, 1H), 6.84 (dd, J=7.0, 5.0 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H),4.35-4.15 (m, 2H), 4.15-3.99 (m, 2H), 2.26-2.14 (m, 1H), 1.90-1.68 (m,2H), 1.64-1.55 (m, 1H), 1.54-1.31 (m, 12H).

Step B:(1S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To the title compound from Step A (130 mg, 0.4 mmol) in EtOAc was added4M HCl in dioxane. After 3 h, the reaction was concentrated, neutralizedwith 5% Na₂CO₃ and extracted with DCM. The combined organics were dried(Na₂SO₄) to give the title compound from step B as a white solid thatwas used without further purification. MS (ESI) mass calcd. forC₁₂H₁₆N₂O, 204.1; m/z found 205.1 [M+H]⁺.

Step C:(5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.To the title compound of Step B (50 mg, 0.18 mmol) in DMF (1.4 mL) wasadded DIPEA (0.078 mL, 0.45 mmol), intermediate A-7 (43 mg, 0.2 mmol)and HATU (75 mg, 0.2 mmol). Upon completion of the reaction,purification was performed using Agilent prep method A to give the titlecompound. MS (ESI) mass calcd. for C₂₃H₂₁FN₄O₂, 404.2; m/z found 405.2[M+H]⁺. ¹H NMR (CDCl₃): 8.78 (d, J=4.9 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H),8.26-8.21 (m, 2H), 7.60-7.50 (m, 1H), 7.23-7.00 (m, 3H), 6.90-6.82 (m,1H), 6.78-6.71 (m, 0.5H), 6.59-6.51 (m, 0.5H), 4.88-4.78 (m, 1H),4.26-4.09 (m, 1H), 4.09-3.95 (m, 1H), 3.92-3.79 (m, 1H), 2.39-2.18 (m,1H), 2.04-1.86 (m, 1H), 1.81-1.31 (m, 5H).

Example 2(±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10, 5-fluoro-2-(pyrimidin-2-yl)benzoic acid withintermediate A-9 and HATU with HBTU to give the title compound. MS (ESI)mass calcd. for C₂₃H₂₃N₅O₂, 401.2; m/z found 402.2 [M+H]⁺. ¹H NMR(DMSO-D₆): 8.92 (d, J=4.9 Hz, 1H), 8.84 (d, J=4.9 Hz, 1H), 8.32 (t,J=8.3 Hz, 1H), 8.24 (dd, J=5.0, 1.4 Hz, 0.5H), 8.15 (dd, J=5.0, 1.5 Hz,0.5H), 7.76-7.69 (m, 0.5H), 7.69-7.62 (m, 0.5H), 7.52-7.42 (m, 1.5H),7.34 (d, J=8.1 Hz, 0.5H), 7.05-6.92 (m, 1H), 6.87 (d, J=8.3 Hz, 0.5H),6.68 (d, J=8.3 Hz, 0.5H), 4.60-4.56 (m, 1H), 4.19 (td, J=10.3, 3.7 Hz,1H), 4.06 (dt, J=10.4, 5.3 Hz, 1H), 3.86 (t, J=4.0 Hz, 0.5H), 3.77 (d,J=4.1 Hz, 0.5H), 2.56 (s, 1.5H), 2.39-2.15 (m, 1H), 2.06 (s, 1.5H),1.88-1.33 (m, 6H).

Example 3A(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S*,2R*,4R*)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

and Example 3B(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1R*,2S*,4S*)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μM250×20 mm) resolution of Example 2 (538 mg) using 70% CO₂/30% EtOH asthe mobile phase to give enantiomer A (230 mg, 1st eluting enantiomer)and enantiomer B (226 mg, 2^(nd) eluting enantiomer). The enantiomericpurity was confirmed by analytical SFC using a CHIRALPAK AD (250×4.6 mm)and a mobile phase of 70% CO₂, 30% EtOH containing 0.3% iPrNH₂ over 7minutes. (Example 3A: >98% single enantiomer, 4.00 min retention time;Example 3B>98% single enantiomer, 5.12 min retention time). Example 3A:MS (ESI) mass calcd. for C₂₃H₂₃N₅O₂, 401.2; m/z found 402.1 [M+H]⁺. ¹HNMR (CDCl₃): 8.83 (d, J=4.8 Hz, 0.8H), 8.72 (d, J=4.8 Hz, 1.2H),8.43-8.37 (m, 1H), 8.19-8.09 (m, 1H), 7.59-7.48 (m, 1H), 7.28 (d, J=8.0Hz, 0.4H), 7.19-7.16 (m, 1.6H), 6.88-6.81 (m, 1H), 6.76 (dt, J=8.4, 1.0Hz, 0.4H), 6.57 (dt, J=8.3, 0.9 Hz, 0.6H), 4.92-4.84 (m, 1H), 4.38-4.23(m, 1H), 4.17 (ddd, J=15.4, 10.3, 5.7 Hz, 1H), 3.97-3.87 (m, 1H), 2.62(s, 1H), 2.39-2.18 (m, 2.5H), 2.11-1.81 (m, 2H), 1.74 (dd, J=12.3, 8.6Hz, 0.5H), 1.68-1.36 (m, 4H).

Example 3B

MS (ESI) mass calcd. for C₂₃H₂₃N₅O₂, 401.2; m/z found 402.1 [M+H]⁺.

Example 4(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10, intermediate A-7 with intermediate A-21 and HATU withHBTU to give the title compound. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂,390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.20-8.07 (m,2H), 7.84-7.75 (m, 2H), 7.61-7.49 (m, 1H), 7.31 (d, J=8.4 Hz, 0.4H),7.19 (d, J=8.4 Hz, 0.6H), 6.87-6.83 (m, 1H), 6.76 (dt, J=8.4, 0.9 Hz,0.4H), 6.57 (dt, J=8.3, 0.9 Hz, 0.6H), 4.91-4.81 (m, 1H), 4.32-4.07 (m,2H), 3.96-3.84 (m, 1H), 2.62 (s, 1.2H), 2.40-2.17 (m, 2.8H), 2.13-1.94(m, 1H), 1.94-1.68 (m, 1.8H), 1.68-1.37 (m, 3.2H).

Example 5A(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

and Example 5B(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1R,2S,4S)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μM250×20 mm) resolution of Example 4 (555 mg) using 70% CO₂/30% EtOH asthe mobile phase to give enantiomer A (264 mg, 1st eluting enantiomer)and enantiomer B (248 mg, 2^(nd) eluting enantiomer). The enantiomericpurity was confirmed by analytical SFC using a CHIRALPAK AD (250×4.6 mm)and a mobile phase of 70% CO₂, 30% EtOH containing 0.3% iPrNH₂ over 7minutes. (Example 5A: >98% single enantiomer, 2.80 min retention time;Example 5B>98% single enantiomer, 3.90 min retention time). Example 5A:MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺.Example 5B: MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2[M+H]⁺.

Example 6(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate A-7 withintermediate A-21. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found391.2 [M+H]⁺. [α]_(D) ²⁰ +11.4° (c 0.88, CHCl₃). ¹H NMR (CDCl₃):8.19-8.06 (m, 2H), 7.83-7.73 (m, 2H), 7.61-7.48 (m, 1H), 7.30 (d, J=8.4Hz, 0.4H), 7.19 (d, J=8.4 Hz, 0.6H), 6.89-6.81 (m, 1H), 6.78-6.73 (m,0.4H), 6.61-6.52 (m, 0.6H), 4.91-4.81 (m, 1H), 4.32-4.08 (m, 2H),3.96-3.84 (m, 1H), 2.62 (s, 1.2H), 2.39-2.18 (m, 2.8H), 2.11-1.94 (m,1.5H), 1.94-1.37 (m, 4.5H).

Example 7(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Step A Method A: (±)-tert-butyl2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Tri-n-butylphosphine (1.8 mL, 7.8 mmol) was added to intermediate B-10(830 mg, 3.7 mmol) and 5-fluoropyridin-2(1H)-one (500 mg, 4.4 mmol) inTHF (11 mL) under nitrogen bubbling at rt. After 5 min of stirring, DEAD(1.4 mL, 7.1 mmol) was added and the mixture was stirred at 50° C. for18 hours. The mixture was concentrated and purified silica gelchromatography (0-15% EtOAc in Heptane) to give the title compound ofstep A (590 mg, 45%) as a white solid.

Step A Method B: (±)-tert-butyl2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to intermediate B-6 substituting intermediate B-9with (±)-B-9 and 2-fluropyridine with 2,5-difluoropyridine. MS (ESI)mass calcd. for C₁₇H₂₃FN₂O₃, 322.2; m/z found 323.0 [M+H]⁺. ¹H NMR(CDCl₃): 8.02-7.87 (m, 1H), 7.41-7.27 (m, 1H), 6.70 (dd, J=9.1, 3.6 Hz,1H), 4.39-4.10 (m, 2H), 4.09-3.89 (m, 2H), 2.25-2.09 (m, 1H), 1.91-1.26(m, 15H).

Step B:(±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.Prepared analogous to Example 1 substituting(±)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylatewith the title compound from Step A. ¹H NMR (CDCl₃): 7.96 (d, J=3.1 Hz,1H), 7.33 (ddd, J=9.0, 7.6, 3.1 Hz, 1H), 6.70 (dd, J=9.0, 3.6 Hz, 1H),4.09-3.98 (m, 2H), 3.72-3.56 (m, 2H), 2.22-1.99 (m, 3H), 1.72-1.53 (m,3H), 1.49-1.34 (m, 1H).

Step C:(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone.Prepared analogous to Example 1 substituting5-fluoro-2-(pyrimidin-2-yl)benzoic acid with6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd.for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2.

Example 8A((1S,2R,4R)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

and Example 8B((1R,2S,4S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μM250×20 mm) resolution of Example 7 (259 mg) using 70% CO₂/30% mixture ofEtOH/i-PrOH (50/50 v/v) as the mobile phase to give enantiomer A (72 mg,1st eluting enantiomer) and enantiomer B (84 mg, 2^(nd) elutingenantiomer). The enantiomeric purity was confirmed by analytical SFCusing a CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 70% CO₂, 15%EtOH, 15% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (Example 8A: 100%single enantiomer, 3.10 min retention time; Example 8B 100% singleenantiomer, 4.58 min retention time). Example 8A: MS (ESI) mass calcd.for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺. Example 8B: MS (ESI)mass calcd. for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺.

Example 9(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 withintermediate A-37. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/zfound 408.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.03-7.95 (m, 1H), 7.81-7.70 (m,3H), 7.38-7.11 (m, 3H), 6.72 (dd, J=9.0, 3.6 Hz, 0.5H), 6.52 (dd, J=9.0,3.5 Hz, 0.5H), 4.86-4.74 (m, 1H), 4.15-3.68 (m, 3H), 2.46-2.37 (s,1.6H), 2.32-1.78 (m, 4.4H), 1.72-1.22 (m, 4H).

Example 10A((1S,2R,4R)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

and Example 10B((1R,2S,4S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μM250×20 mm) resolution of Example 9 (290 mg) using 60% CO₂/40% i-PrOH asthe mobile phase to give enantiomer A (140 mg, 1st eluting enantiomer)and enantiomer B (134 mg, 2^(nd) eluting enantiomer). The enantiomericpurity was confirmed by analytical SFC using a CHIRALPAK AD-H (250×4.6mm) and a mobile phase of 60% CO₂, 40% iPrOH containing 0.3% iPrNH₂ over7 minutes. (Example 10A: >98% single enantiomer, 2.42 min retentiontime; Example 10B>98% single enantiomer, 3.20 min retention time).

Example 11(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(thiophen-2-yl)phenyl)methanone

To (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane(35 mg, 0.2 mmol) in DCM (2.5 mL) was added TEA (25 μL, 0.2 mmol))followed by 2-(thiophen-2-yl)benzoyl chloride (40 mg, 0.2 mmol) in DCM(2.5 mL). After 18 h, the reaction was diluted with DCM and washed withH₂O. The aqueous layer was extracted DCM (1×). The combined organicswere dried (Na₂SO₄). Purification via silica gel chromatography (50-100%EtOAc in hexanes) gave the title compound (37 mg, 57%). MS (ESI) masscalcd. for C₂₃H₂₁FN₂O₂S, 408.1; m/z found 409.1 [M+H]⁺.

Example 12A((1S*,2R*,4R*)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(thiophen-2-yl)phenyl)methanone

and Example 12B((1R*,2S*,4S*)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(thiophen-2-yl)phenyl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AS-H 5 μM250×20 mm at 40° C.) resolution of Example 11 using 4.2 mL/min MeOH with0.2% TEA, 37 mL/min CO₂ as the mobile phase to give enantiomer A (1steluting enantiomer) and enantiomer B (2^(nd) eluting enantiomer).

Example 12A: MS (ESI) mass calcd. for C₂₃H₂₁FN₂O₂S, 408.2; m/z found409.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.97 (dd, J=11.0, 3.0 Hz, 1H), 7.54-7.20(m, 6.5H), 7.01 (dd, J=5.0, 3.7 Hz, 1.5H), 6.71 (dd, J=9.1, 3.5 Hz,0.5H), 6.45 (dd, J=9.0, 3.6 Hz, 0.5H), 4.83-4.63 (m, 1H), 4.18-3.38 (m,3H), 2.70-0.40 (m, 7H).

Example 12B: MS (ESI) mass calcd. for C₂₃H₂₁FN₂O₂S, 408.2; m/z found409.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.97 (dd, J=11.0, 3.0 Hz, 1H), 7.54-7.20(m, 6.5H), 7.01 (dd, J=5.0, 3.7 Hz, 1.5H), 6.71 (dd, J=9.1, 3.5 Hz,0.5H), 6.45 (dd, J=9.0, 3.6 Hz, 0.5H), 4.83-4.63 (m, 1H), 4.18-3.38 (m,3H), 2.70-0.40 (m, 7H).

Example 13(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-7-azabicyclo[2.2.1]heptan-2-ylmethanol hydrochloride. Tointermediate B-10 (1.1 g, 4.9 mmol) in MeOH (1 mL) was added 4M HCl indioxane (3 mL). After 6 h, the reaction was concentrated to give thetitle compound that was used without further purification.

Step B:((±)-2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.To the title compound of Step A in DMF was added TEA,5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and HATU. After 18 h, H₂Owas added and the mix extracted with EtOAc (2×). The combined organicswere washed with brine and dried (Na₂SO₄). Silica gel chromatography(1-7% 2M NH₃/MeOH in DCM) gave the title compound (371 mg, 46%). MS(ESI) mass calcd. for C₁₇H₂₀N₄O₂, 312.2; m/z found 313.2 [M+H]⁺.

Step C:(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.To the title compound of step B (33 mg, 0.1 mmol) in THF (2 mL) wasadded NaOtBu (16 mg, 0.16 mmol). The reaction was then heated at refluxfor 15 min and 2-chloro-4-trifluromethylpyrimidine (19 mg, 0.16 mmol)was added. The reaction was heated at reflux temperature for 1 h, cooledto rt, diluted with H₂O and extracted with DCM (2×). The combinedorganics were dried (Na₂SO₄). Purification via silica gel chromatography(0.5-4% 2M NH₃/MeOH in DCM gave the title compound (28 mg, 57%). MS(ESI) mass calcd. for C₂₂H₂₁F₃N₆O₂, 457.2; m/z found 458.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.82-8.72 (m, 1H), 7.86-7.69 (m, 3H), 7.36-7.10 (m, 3H),4.85 (m, 1H), 4.47 (t, J=10.1 Hz, 0.5H), 4.20-3.98 (m, 1.5H), 3.90 (d,J=4.7 Hz, 0.5H), 3.78 (t, J=4.5 Hz, 0.5H), 2.51-2.20 (m, 3H), 2.14-1.82(m, 2H), 1.78-1.17 (m, 5H).

Example 14(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with2-chloro-5-(trifluoromethyl)pyridine. MS (ESI) mass calcd. forC₂₃H₂₂F₃N₅O₂, 457.2; m/z found 458.2 [M+H]⁺.

Example 15(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((3-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with2-chloro-3-(trifluoromethyl)pyridine. MS (ESI) mass calcd. forC₂₃H₂₂F₃N₅O₂, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.36-8.26(m, 1H), 7.91-7.69 (m, 4H), 7.36-7.29 (m, 0.5H), 7.25-7.16 (m, 1H),7.13-7.07 (m, 0.5H), 6.97 (dd, J=7.5, 5.1 Hz, 1H), 4.87-4.70 (m, 1H),4.53-4.34 (m, 0.5H), 4.25-4.06 (m, 1H), 3.92 (t, J=10.9 Hz, 0.5H),3.85-3.71 (m, 1H), 2.46-2.40 (m, 1.5H), 2.39-2.19 (m, 1.5H), 2.04-1.79(m, 3H), 1.72-1.19 (m, 4H).

Example 16(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with2-chloro-6-(trifluoromethyl)pyridine. MS (ESI) mass calcd. forC₂₃H₂₂F₃N₅O₂, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.87-7.63(m, 4H), 7.37-7.11 (m, 3H), 6.92 (d, J=8.4 Hz, 0.5H), 6.73 (d, J=8.4 Hz,0.5H), 4.88-4.75 (m, 1H), 4.20-3.84 (m, 2H), 3.81-3.67 (m, 1H),2.49-2.36 (s, 2H), 2.34-2.13 (m, 1H), 2.08-1.77 (m, 3H), 1.76-1.10 (m,4H).

Example 17(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-4-(methyl)pyridine.MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.10-7.91 (m, 1H), 7.87 (d, J=3.7 Hz, 2H), 7.82-7.70 (m,1H), 7.50-7.42 (m, 1H), 7.34-7.24 (m, 0.5H), 7.16-7.08 (m, 0.5H),6.90-6.80 (m, 1H), 6.77-6.66 (m, 0.4H), 6.59-6.45 (m, 0.6H), 4.68 (q,J=4.0, 3.3 Hz, 1H), 4.16-3.71 (m, 3H), 2.49-2.18 (m, 5H), 1.94-1.17 (m,8H).

Example 18(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-6-(methyl)pyridine.MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.89 (d, J=1.3 Hz, 2H), 7.82-7.66 (m, 1.5H), 7.61 (dd,J=8.3, 7.3 Hz, 0.5H), 7.43 (ddd, J=8.3, 1.9, 0.9 Hz, 0.5H), 7.35-7.26(m, 1H), 7.16-7.09 (m, 0.5H), 6.88 (dd, J=16.1, 7.3 Hz, 1H), 6.76 (d,J=8.4 Hz, 0.5H), 6.53 (d, J=8.3 Hz, 0.5H), 4.74-4.64 (m, 1H), 4.24-4.04(m, 1H), 4.02-3.76 (m, 2H), 2.55-2.21 (m, 5H), 2.05-1.23 (m, 8H).

Example 19(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-5-(methyl)pyridine.MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.10-7.58 (m, 4H), 7.43-7.29 (m, 1.5H), 7.26-7.11 (m,1.5H), 6.66 (d, J=8.4 Hz, 0.5H), 6.45 (d, J=8.4 Hz, 0.5H), 4.86-4.71 (m,1H), 4.17-3.66 (m, 3H), 2.46-2.38 (s, 1.2H), 2.31-2.14 (m, 3.8H),2.01-1.79 (m, 2H), 1.71-1.18 (m, 6H).

Example 20(±)-(2-(((3,6-dimethylpyrazin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with3-chloro-2,5-dimethylpyrazine. MS (ESI) mass calcd. for C₂₃H₂₆N₆O₂,418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 7.88-7.84 (m,1H), 7.81-7.72 (m, 2.5H), 7.36-7.12 (m, 2H), 7.11-7.06 (m, 0.5H),4.86-4.75 (m, 1H), 4.26-4.15 (m, 0.5H), 4.08 (dd, J=11.0, 5.5 Hz, 1H),3.86-3.71 (m, 1.5H), 2.48-2.34 (m, 6H), 2.34-2.13 (m, 3H), 1.96-1.25 (m,7H).

Example 21(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((3-(trifluoromethyl)quinoxalin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with2-chloro-3-(trifluoromethyl)quinoxaline. MS (ESI) mass calcd. forC₂₆H₂₃F₃N₆O₂, 508.2; m/z found 509.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.16-8.09(m, 1H), 7.97-7.62 (m, 6H), 7.37-7.23 (m, 1H), 7.19-7.06 (m, 1H), 4.87(t, J=4.7 Hz, 0.5H), 4.80 (d, J=4.8 Hz, 0.5H), 4.71-4.56 (m, 0.5H),4.38-4.22 (m, 1H), 4.16-4.01 (m, 0.5H), 3.87-3.73 (m, 1H), 2.49-2.23 (m,4H), 2.05-1.24 (m, 6H).

Example 22(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 withintermediate A-1. MS (ESI) mass calcd. for C₂₁H₂₀FN₅O₂, 393.2; m/z found394.2 [M+H]⁺. ¹H NMR (400 MHz, MeOD) 8.02-7.78 (m, 4H), 7.62-7.53 (m,0.5H), 7.49-7.28 (m, 3H), 7.13-7.01 (m, 0.5H), 6.75 (dd, J=9.0, 3.6 Hz,0.5H), 6.51 (dd, J=9.0, 3.6 Hz, 0.5H), 4.85-4.71 (m, 1H), 4.21-4.03 (m,1H), 4.02-3.72 (m, 2H), 2.39-2.09 (m, 1H), 2.04-1.16 (m, 6H).

Example 23(±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(quinolin-8-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 withquinoline-8-carboxylic acid. MS (ESI) mass calcd. for C₂₂H₂₀FN₃O₂,377.2; m/z found 378.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.95-8.69 (m,1H), 8.16 (dd, J=8.3, 1.8 Hz, 0.4H), 8.11-7.81 (m, 2H), 7.81-7.67 (m,1H), 7.64-7.51 (m, 1H), 7.47-7.09 (m, 2.6H), 6.79 (dd, J=9.0, 3.6 Hz,0.5H), 6.25 (s, 0.5H), 5.08-4.96 (m, 1H), 4.29 (s, 0.7H), 4.13-3.94 (m,1.3H), 3.65-3.45 (m, 1H), 2.47-2.02 (m, 2H), 2.02-1.30 (m, 5H).

Example 24(±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(naphthalen-1-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with1-naphthoic acid. MS (ESI) mass calcd. for C₂₃H₂₁FN₂O₂, 376.2; m/z found377.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.10-7.95 (m, 1.5H), 7.92-7.83(m, 1.5H), 7.81-7.71 (m, 1H), 7.58-7.31 (m, 4H), 7.25-7.13 (m, 1H), 6.77(dd, J=9.0, 3.6 Hz, 0.5H), 6.36-6.24 (m, 0.5H), 5.04-4.92 (m, 1H),4.30-4.13 (m, 1H), 4.07-3.84 (m, 1H), 3.81-3.64 (m, 1H), 2.44-2.30 (m,0.5H), 2.27-2.00 (m, 1.5H), 1.89-1.37 (m, 5H).

Example 25(±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-methylnaphthalen-1-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with2-methyl-1-naphthoic acid. ¹H NMR (CDCl₃): 8.06-7.86 (m, 1H), 7.85-7.62(m, 2.6H), 7.60-7.54 (m, 0.2H), 7.49-7.21 (m, 3.4H), 7.13 (m, 0.8H),6.77 (ddd, J=12.7, 9.0, 3.6 Hz, 0.6H), 6.43 (dd, J=9.0, 3.6 Hz, 0.2H),6.03 (dd, J=9.0, 3.6 Hz, 0.2H), 5.11-4.99 (m, 0.9H), 4.38-4.09 (m,1.2H), 4.08-3.82 (m, 0.7H), 3.69-3.43 (m, 1.2H), 2.58-2.27 (m, 3.5H),2.23-1.97 (m, 1.5H), 1.92-1.28 (m, 5H).

Example 26(±)-2-(1H-pyrazol-1-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with2-(1H-pyrazol-1-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₁FN₄O₂,392.2; m/z found 393.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.98 (dd, J=8.3, 3.1 Hz,1H), 7.91-7.83 (m, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.64-7.23 (m, 4.5H),6.99 (t, J=7.4 Hz, 0.5H), 6.71 (dd, J=9.0, 3.6 Hz, 0.5H), 6.47-6.34 (m,1.5H), 4.79-4.63 (m, 1H), 4.03-3.65 (m, 2H), 3.66-3.54 (m, 1H),2.27-2.03 (m, 1H), 1.86-0.74 (m, 6H).

Example 27(±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-phenylfuran-2-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with3-phenylfuran-2-carboxylic acid. MS (ESI) mass calcd. for C₂₂H₂₁FN₂O₃,392.2; m/z found 393.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.05-7.82 (m, 1H),7.59-7.44 (m, 7H), 6.77-6.40 (m, 2H), 4.85-4.61 (m, 1H), 4.45-4.29 (m,0.5H), 4.24-4.08 (m, 0.5H), 4.06-3.76 (m, 2H), 2.32-2.11 (m, 1H),2.01-0.83 (m, 6H).

Example 28(±)-(2-ethoxynaphthalen-1-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with2-ethoxy-1-naphthoic acid. MS (ESI) mass calcd. for C₂₅H₂₅FN₂O₃, 420.2;m/z found 421.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.03 (d, J=3.0 Hz, 0.2H), 7.95(dd, J=8.1, 3.1 Hz, 0.5H), 7.86-7.70 (m, 2.6H), 7.69-7.63 (m, 0.3H),7.60-7.55 (m, 0.3H), 7.50-7.00 (m, 4.2H), 6.76 (ddd, J=9.3, 6.1, 3.6 Hz,0.5H), 6.44 (dd, J=9.0, 3.5 Hz, 0.2H), 6.03 (dd, J=9.0, 3.6 Hz, 0.2H),5.08-4.97 (m, 1H), 4.35-3.92 (m, 3.3H), 3.91-3.76 (m, 0.5H), 3.68-3.52(m, 1.2H), 2.44-2.27 (m, 0.8H), 2.20-1.93 (m, 2H), 1.85-1.18 (m, 7.2H).

Example 29(±)-(5-(2-fluorophenyl)-2-methylthiazol-4-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with5-(2-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) masscalcd. for C₂₃H₂₁F₂N₃O₂S, 441.2; m/z found 442.2 [M+H]⁺. ¹H NMR (CDCl₃):7.99-7.93 (m, 1H), 7.53-7.44 (m, 1H), 7.36-7.09 (m, 3.5H), 7.04 (ddd,J=9.8, 8.5, 1.2 Hz, 0.5H), 6.66 (ddd, J=15.9, 9.0, 3.6 Hz, 1H),4.79-4.68 (m, 1H), 4.27-4.21 (m, 0.5H), 4.07 (t, J=4.6 Hz, 0.5H),3.96-3.73 (m, 2H), 2.74 (s, 1.5H), 2.42 (s, 1.5H), 2.23-2.11 (m, 1H),1.89-1.57 (m, 2H), 1.54-1.24 (m, 3.5H), 0.92-0.81 (m, 0.5H).

Example 30(±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 withintermediate A-10. MS (ESI) mass calcd. for C₂₁H₁₉F₂N₅O₂, 411.2; m/zfound 412.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.98 (dd, J=7.4, 3.0 Hz, 1H), 7.86(ddd, J=21.7, 8.9, 4.7 Hz, 1H), 7.81-7.75 (m, 1.5H), 7.38-7.03 (m,3.5H), 6.72 (dd, J=9.0, 3.6 Hz, 0.5H), 6.52 (dd, J=9.0, 3.6 Hz, 0.5H),4.85-4.75 (m, 1H), 4.17-4.02 (m, 1H), 4.02-3.83 (m, 1H), 3.83-3.75 (m,1H), 2.34-2.15 (m, 1H), 2.03-1.80 (m, 1H), 1.74-1.20 (m, 5H).

Example 31(±)-(2-fluoro-6-(pyrimidin-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 withintermediate A-6. MS (ESI) mass calcd. for C₂₃H₂₀F₂N₄O₂, 422.2; m/zfound 423.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.93-8.61 (m, 1.8H), 8.15-7.92 (m,1.6H), 7.56-7.05 (m, 4.3H), 6.94 (t, J=8.6 Hz, 0.3H), 6.73 (ddd, J=8.9,5.2, 3.5 Hz, 0.6H), 6.59-6.35 (m, 0.4H), 4.99-4.79 (m, 1H), 4.31 (t,J=9.9 Hz, 0.3H), 4.25-3.63 (m, 2.7H), 2.47-1.11 (m, 7H).

Example 32(±)-(5-fluoro-2-(pyrimidin-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with5-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₃H₂₀F₂N₄O₂, 422.2; m/z found 423.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃)8.78 (d, J=4.9 Hz, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.22 (ddd, J=20.6, 8.7,5.5 Hz, 1H), 8.01-7.93 (m, 1H), 7.37-7.27 (m, 1H), 7.23-7.13 (m, 1.5H),7.13-6.99 (m, 1.5H), 6.72 (dd, J=9.0, 3.5 Hz, 0.5H), 6.52 (dd, J=9.0,3.5 Hz, 0.5H), 4.90-4.75 (m, 1H), 4.25-3.91 (m, 2H), 3.91-3.78 (m, 1H),2.39-2.15 (m, 1H), 2.08-1.13 (m, 6H).

Example 33(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with5-methyl-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₄H₂₃FN₄O₂, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.81-8.68(m, 2H), 8.09 (dd, J=9.9, 8.0 Hz, 1H), 7.98 (dd, J=8.6, 3.1 Hz, 1H),7.41-7.24 (m, 1.5H), 7.22-7.16 (m, 1H), 7.16-7.09 (m, 1.5H), 6.73 (dd,J=9.1, 3.6 Hz, 0.5H), 6.52 (dd, J=9.0, 3.6 Hz, 0.5H), 4.88-4.77 (m, 1H),4.21-4.01 (m, 1H), 4.01-3.89 (m, 1H), 3.88-3.76 (m, 1H), 2.42 (s, 1.6H),2.35-2.10 (m, 1H), 2.07-1.81 (m, 2.4H), 1.81-1.16 (m, 5H).

Example 34(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-ylmethanone

Step A: (±)-2-(-7-azabicyclo[2.2.1]heptan-2-ylmethoxy)quinoxaline. Tointermediate B-10 (240 mg, 1.1 mmol) in THF (4 mL) was added NaOtBu (130mg, 1.4 mmol). The reaction was heated at reflux for 15 min and2-chloroquinoxaline (207 mg, 1.3 mmol) was added. After 45 min, thereaction was cooled to rt and ½ saturated NH₄Cl (aq) was added. Thesolution was made slightly basic with 5% Na₂CO₃ (aq) and extracted withDCM (3×). The combined organics were dried (Na₂SO₄). The resultingcompound was treated with TFA in DCM. After the reaction was complete,the reaction was concentrated, neutralized with 5% Na₂CO₃ and extractedwith DCM. The combined organics were dried (Na₂SO₄). Purification viasilica gel chromatography (1-7% (2M NH₃ in MeOH)/DCM) gave the titlecompound (208 mg, 78%). MS (ESI) mass calcd. for C₁₅H₁₇N₃O, 255.1; m/zfound 256.2 [M+H]⁺.

Step B:(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 7 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with intermediate A-1and (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptanewith the title compound of Step A. MS (ESI) mass calcd. for C₂₄H₂₂N₆O₂,426.2; m/z found 427.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.49 (s, 0.5H), 8.31-8.21(s, 0.5H), 8.08-7.98 (m, 1H), 7.95-7.75 (m, 3.4H), 7.75-7.66 (m, 1.1H),7.65-7.50 (m, 1.7H), 7.50-7.39 (m, 1.1H), 7.36-7.28 (m, 1H), 7.24-7.13(m, 0.7H), 4.92-4.80 (m, 1H), 4.47-4.28 (m, 1H), 4.22-4.07 (m, 1H),3.87-3.77 (m, 1H), 2.46-2.23 (m, 1.7H), 2.07-1.83 (m, 1.3H), 1.82-1.29(m, 4H).

Example 35(±)-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 34 substituting intermediate A-1 withintermediate A-11. MS (ESI) mass calcd. for C₂₄H₂₁FN₆O₂, 444.2; m/zfound 445.2 [M+H]. ¹H NMR (CDCl₃): 8.52-8.47 (m, 0.5H), 8.27-8.21 (m,0.4H), 8.07-7.95 (m, 1H), 7.91-7.09 (m, 7.8H), 6.72-6.63 (m, 0.3H),4.98-4.87 (m, 1H), 4.63-4.54 (dd, J=10.7, 9.1 Hz, 0.5H), 4.46-4.29 (m,1H), 4.20-4.04 (m, 0.5H), 3.96-3.76 (m, 1H), 2.51-2.23 (m, 1H),2.17-1.88 (m, 1H), 1.84-1.19 (m, 5H).

Example 36(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 34 substituting intermediate A-1 withintermediate A-37. MS (ESI) mass calcd. for C₂₅H₂₄N₆O₂, 440.2; m/z found441.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.49 (s, 0.5H), 8.26 (s, 0.5H), 8.03 (ddd,J=8.3, 4.4, 1.4 Hz, 1H), 7.90-7.74 (m, 3H), 7.74-7.65 (m, 1H), 7.59(dddd, J=8.3, 7.0, 4.8, 1.4 Hz, 1H), 7.33 (ddd, J=8.3, 1.9, 0.9 Hz,0.6H), 7.29-7.22 (m, 1H), 7.21-7.10 (m, 1.4H), 4.90-4.79 (m, 1H),4.46-3.98 (m, 2H), 3.91-3.72 (m, 1H), 2.47-2.20 (m, 4H), 2.05-1.22 (m,6H).

Example 37(±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 34 substituting intermediate A-1 withintermediate A-10. MS (ESI) mass calcd. for C₂₄H₂₁FN₆O₂, 444.2; m/zfound 445.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.55-8.44 (m, 0.5H), 8.36-8.23 (m,0.5H), 8.08-8.00 (m, 1H), 7.90-7.55 (m, 5H), 7.49-7.09 (m, 3H),4.91-4.82 (m, 1H), 4.50-4.29 (m, 1H), 4.23-4.07 (m, 1H), 3.82 (dd,J=10.0, 5.0 Hz, 1H), 2.48-2.25 (m, 1H), 2.09-1.88 (m, 1H), 1.82-1.31 (m,5H).

Example 38(±)-(5-methyl-2-(pyrimidin-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 34 substituting intermediate A-1 withintermediate A-34. MS (ESI) mass calcd. for C₂₇H₂₅N₅O₂, 451.2; m/z found452.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.87-8.79 (m, 1H), 8.75-8.68 (m, 1H), 8.49(s, 0.5H), 8.27 (s, 0.5H), 8.14-7.98 (m, 2H), 7.85 (ddd, J=16.5, 8.3,1.5 Hz, 1H), 7.74-7.66 (m, 1H), 7.64-7.54 (m, 1H), 7.35-7.29 (m, 0.5H),7.24-7.19 (m, 0.5H), 7.18-7.07 (m, 2H), 4.94-4.83 (m, 1H), 4.52-4.07 (m,2H), 3.93-3.82 (m, 1H), 2.51-2.20 (m, 2.6H), 2.08-1.83 (m, 1.4H),1.81-1.12 (m, 6H).

Example 39(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Step A:(±)-2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.Prepared analogous to Example 34 substituting 2-chloroquinoxaline with2-chloro-4,6-dimethylpyrimidine. ¹H NMR (CDCl₃): 6.65 (s, 1H), 4.21-3.99(m, 2H), 3.74-3.56 (m, 2H), 2.39 (s, 6H), 2.14 (ddd, J=9.0, 5.1, 3.7 Hz,1H), 1.86 (s, 2H), 1.67-1.49 (m, 2H), 1.47-1.30 (m, 2H).

Step B:(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.Prepared analogous to Example 7 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and(±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptanewith the title compound of Step A. MS (ESI) mass calcd. for C₂₃H₂₆N₆O₂,418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.83-7.70 (m, 2.5H),7.35-7.10 (m, 2.5H), 6.71-6.65 (m, 1H), 4.87-4.72 (m, 1H), 4.34 (dd,J=10.5, 8.8 Hz, 0.5H), 4.14-3.89 (m, 2H), 3.79-3.70 (m, 0.5H), 2.48-2.18(m, 7.5H), 2.07-1.83 (m, 2.5H), 1.79-1.18 (m, 6H).

Example 40(±)-2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-5-phenylisoxazol-4-yl)methanone

Prepared analogous to Example 39 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with3-methyl-5-phenylisoxazole-4-carboxylic acid. MS (ESI) mass calcd. forC₂₄H₂₆N₄O₃, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.67 (m, 2H),7.50-7.31 (m, 3H), 6.69 (d, J=6.7 Hz, 1H), 4.74 (dd, J=10.8, 5.1 Hz,1H), 4.17 (dd, J=10.8, 9.2 Hz, 0.5H), 3.85-3.78 (m, 1H), 3.70 (d, J=4.9Hz, 0.5H), 3.64-3.42 (m, 1H), 2.55 (s, 1.4H), 2.49 (s, 1.6H), 2.43 (s,3H), 2.39 (s, 3H), 2.29-2.07 (m, 1H), 1.90-1.55 (m, 2H), 1.53-1.06 (m,3H), 0.76-0.53 (m, 1H).

Example 41(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-ethoxynaphthalen-1-yl)methanone

Prepared analogous to Example 39 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-ethoxy-1-naphthoicacid. ¹H NMR (CDCl₃): 7.91-7.70 (m, 2.5H), 7.67-7.54 (m, 0.5H),7.49-7.38 (m, 0.8H), 7.37-7.28 (m, 0.8H), 7.27-7.16 (m, 0.9H), 7.10-7.02(m, 0.5H), 6.70 (s, 0.2H), 6.65 (s, 0.5H), 6.53 (s, 0.3H), 5.09-4.95 (m,1H), 4.56-4.47 (m, 0.5H), 4.28-3.87 (m, 3.3H), 3.79-3.55 (m, 1.2H),2.46-2.35 (m, 4.5H), 2.28 (s, 1.5H), 2.21-1.95 (m, 2H), 1.85-1.51 (m,3.5H), 1.51-1.24 (m, 4.5H).

Example 42(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-ethoxyphenyl)methanone)

Prepared analogous to Example 39 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-ethoxybenzoicacid. MS (ESI) mass calcd. for C₂₂H₂₇N₃O₃, 381.2; m/z found 382.2[M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.27 (m, 1H), 7.21-7.12 (m, 1H), 6.98-6.92(m, 0.5H), 6.89 (d, J=8.2 Hz, 0.5H), 6.78 (d, J=8.3 Hz, 0.5H), 6.72-6.63(m, 1.5H), 4.89-4.78 (m, 1H), 4.36 (dd, J=10.6, 8.7 Hz, 0.5H), 4.14-3.71(m, 4.5H), 2.45-2.16 (m, 6.5H), 2.06-1.82 (m, 1.5H), 1.82-1.28 (m, 8H).

Example 43(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-fluoro-6-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to Example 39 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with2-fluoro-6-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₄H₂₄FN₅O₂, 433.2; m/z found 434.2 [M+H]⁺. ¹H NMR (CDCl₃): 9.02-8.90(m, 0.7H), 8.82-8.65 (m, 1.3H), 8.14-7.95 (m, 1H), 7.58-7.31 (m, 1H),7.31-7.07 (m, 1.7H), 6.97-6.86 (m, 0.3H), 6.75-6.51 (m, 1H), 4.96-4.83(m, 1H), 4.55 (dd, J=10.3, 9.0 Hz, 0.25H), 4.36 (dd, J=10.6, 8.9 Hz,0.25H), 4.21-3.78 (m, 2.5H), 2.48-1.17 (m, 13H).

Example 44(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to Example 39 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with5-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₄H₂₄FN₅O₂, 433.2; m/z found 434.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.88-8.78(m, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.26 (dd, J=8.7, 5.5 Hz, 0.5H),8.22-8.16 (m, 0.5H), 7.29-7.09 (m, 2H), 7.06-6.97 (m, 1H), 6.68 (s, 1H),4.88-4.81 (m, 1H), 4.40 (t, J=9.7 Hz, 0.5H), 4.25 (t, J=10.8 Hz, 0.5H),4.05 (dd, J=10.2, 6.2 Hz, 0.5H), 3.99-3.91 (m, 1H), 3.89-3.80 (m, 0.5H),2.45-2.21 (m, 7H), 2.05-1.87 (m, 1H), 1.81-1.30 (m, 5H).

Example 45(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to Example 39 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with5-methyl-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₅H₂₇N₅O₂, 429.2; m/z found 430.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.83 (d,J=5.0 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.09 (dd, J=13.6, 8.0 Hz, 1H),7.33-7.10 (m, 3H), 6.68 (d, J=1.4 Hz, 1H), 4.90-4.79 (m, 1H), 4.41 (dd,J=10.4, 8.8 Hz, 0.5H), 4.20 (t, J=10.6 Hz, 0.5H), 4.07-3.94 (m, 1.5H),3.80 (t, J=4.7 Hz, 0.5H), 2.49-2.19 (m, 7H), 2.04-1.89 (m, 3H),1.87-1.47 (m, 4.5H), 1.45-1.29 (m, 1.5H).

Example 46(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(thiophen-2-yl)phenyl)methanone

Prepared analogous to Example 11 substituting(±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptanewith(±)-2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.MS (ESI) mass calcd. for C₂₄H₂₅N₃O₂S, 419.2; m/z found 420.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 7.55-6.83 (m, 7H), 6.75-6.62 (m, 1H), 4.87-4.62(m, 1H), 4.09-3.38 (m, 3H), 2.54-2.32 (m, 6H), 2.32-2.03 (m, 1H),1.97-0.87 (m, 6H).

Example 47(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A:(±)-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.Prepared analogous to Example 49 substituting 5-bromo-2-fluoropyridinewith 2-fluoro-5-(trifluoromethyl)pyridine. MS (ESI) mass calcd. forC₁₃H₁₅F₃N₂O, 272.1; m/z found 273.1, [M+H]⁺.

Step B:(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 1 substituting5-fluoro-2-(pyrimidin-2-yl)benzoic acid with6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid and(1S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylatewith the title compound of Step A. MS (ESI) mass calcd. forC₂₂H₂₁F₃N₆O₂, 458.2; m/z found 459.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.47-8.37(m, 1H), 8.12 (dd, J=13.2, 8.4 Hz, 1H), 7.85-7.69 (m, 3H), 7.32 (dd,J=8.4, 0.6 Hz, 0.5H), 7.22 (dd, J=8.4, 0.6 Hz, 0.5H), 6.88-6.82 (m,0.5H), 6.69-6.59 (m, 0.5H), 4.93-4.81 (m, 1H), 4.39-4.18 (m, 2H),3.94-3.87 (m, 1H), 2.65-2.60 (s, 1.2H), 2.39-2.22 (m, 2.8H), 2.11-1.33(m, 6H).

Example 48(±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 47 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with3-ethoxy-6-methylpicolinic acid. MS (ESI) mass calcd. for C₂₂H₂₄F₃N₃O₃,435.2; m/z found 436.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.43-8.35 (m, 1H),7.79-7.68 (m, 1H), 7.18-7.07 (m, 1H), 7.07-6.96 (m, 1H), 6.86 (d, J=8.7Hz, 0.5H), 6.64 (d, J=8.7 Hz, 0.5H), 4.92-4.86 (m, 1H), 4.29-4.20 (m,1H), 4.19-4.10 (m, 1H), 4.10-3.83 (m, 2H), 3.74 (t, J=3.9 Hz, 1H),2.52-2.47 (s, 1.5H), 2.41-2.32 (m, 0.5H), 2.28-2.18 (m, 2H), 2.07-1.84(m, 2H), 1.78-1.63 (m, 1H), 1.62-1.41 (m, 3H), 1.37 (dt, J=11.8, 7.0 Hz,3H).

Example 49(±)-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Step A:(±)-2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. Tointermediate B-10 (175 mg, 0.8 mmol) in DMF (3.5 mL) at 0° C. was addedNaH (60 wt % in mineral oil, 37 mg, 0.9 mmol). After 30 min,5-bromo-2-fluoropyridine (190 mg, 1.1 mmol) in DMF (0.5 mL) was addeddropwise and the 0° C. ice bath was removed. After 2 h, brine was addedand the reaction extracted with EtOAc (2×). The combined organics werewashed with brine and dried (Na₂SO₄) to give a clear oil which wastreated with TFA and DCM (1:1, 10 mL). After 2 h, the reaction wasconcentrated, dissolved in DCM and neutralized with 5% Na₂CO₃ (aq). Thecombined organics were extracted with DCM (3×) and dried (Na₂SO₄) togive the title compound that was used in subsequent reactions withoutfurther purification. MS (ESI) mass calcd. for C₁₂H₁₅BrN₂O, 282.0; m/zfound 283.1, 285.1 [M+H]⁺. NMR (500 MHz, CDCl₃): 8.17 (d, J=2.5 Hz, 1H),7.63 (dd, J=8.8, 2.5 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.08-3.99 (m, 2H),3.65 (t, J=4.5 Hz, 1H), 3.59 (d, J=4.1 Hz, 1H), 2.12-2.06 (m, 1H), 1.87(s, 1H), 1.68-1.52 (m, 2H), 1.45-1.13 (m, 3H), 0.95-0.76 (m, 1H).

Step B: Prepared analogous to Example 1 substituting5-fluoro-2-(pyrimidin-2-yl)benzoic acid with6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid and(1S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylatewith the title compound of Step A. MS (ESI) mass calcd. forC₂₁H₂₁BrN₆O₂, 468.1; m/z found 469.1, 471.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.20(d, J=2.6 Hz, 0.4H), 8.16 (d, J=2.6 Hz, 0.6H), 8.13 (d, J=8.3 Hz, 0.4H),8.10 (d, J=8.4 Hz, 0.6H), 7.82-7.77 (m, 2H), 7.64 (dd, J=8.8, 2.6 Hz,0.4H), 7.60 (dd, J=8.8, 2.6 Hz, 0.6H), 7.33-7.29 (m, 0.4H), 7.22 (d,J=8.4 Hz, 0.6H), 6.69 (d, J=8.8 Hz, 0.4H), 6.50 (d, J=8.8 Hz, 0.6H),4.84 (dd, J=11.1, 5.2 Hz, 1H), 4.30-4.04 (m, 2H), 3.93-3.85 (m, 1H),2.62 (s, 1.3H), 2.38-2.17 (m, 2.7H), 2.11-1.95 (m, 1H), 1.94-1.77 (m,1H), 1.77-1.40 (m, 4H).

Example 50(±)-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-methoxyphenyl)methanone

Prepared analogous to Example 49 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₂₀BrFN₂O₃,434.1; m/z found 435.1, 437.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.19-8.12 (m, 1H),7.61 (ddd, J=26.6, 8.8, 2.5 Hz, 1H), 7.16-6.98 (m, 2H), 6.96 (dt, J=7.6,1.3 Hz, 0.5H), 6.85-6.81 (m, 0.5H), 6.69 (dd, J=8.8, 0.8 Hz, 0.5H), 6.46(d, J=8.7 Hz, 0.5H), 4.88-4.77 (m, 1H), 4.17-4.06 (m, 1H), 4.03-3.86 (m,4H), 3.81-3.75 (m, 1H), 2.37-2.22 (m, 1H), 2.04-1.40 (m, 6H).

Example 51(±)-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6-methylpyridin-2-yl)methanone

Prepared analogous to Example 49 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with3-ethoxy-6-methylpicolinic acid. MS (ESI) mass calcd. for C₂₁H₂₄BrN₃O₃,445.1; m/z found 446.1, 448.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.17-8.11 (m, 1H),7.61 (ddd, J=19.5, 8.8, 2.6 Hz, 1H), 7.16-7.06 (m, 1H), 7.05-6.96 (m,1H), 6.69 (dd, J=8.8, 0.7 Hz, 0.5H), 6.47 (dd, J=8.8, 0.7 Hz, 0.5H),4.90-4.84 (m, 1H), 4.20-4.10 (m, 1H), 4.09-3.82 (m, 3H), 3.78-3.72 (m,1H), 2.50 (s, 1.4H), 2.38-2.25 (m, 2.6H), 2.04-1.84 (m, 2H), 1.75-1.40(m, 4H), 1.60-1.40 (m, 3H), 1.36 (dt, J=7.8, 7.0 Hz, 3H).

Example 52(±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting5-fluoro-2-(pyrimidin-2-yl)benzoic acid with3-fluoro-2-(pyrimidin-2-yl)benzoic acid and intermediate B-9 withintermediate B-10. MS (ESI) mass calcd. for C₂₃H₂₁FN₄O₂, 404.2; m/zfound 405.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.81 (dd, J=18.0, 4.9 Hz, 2H),8.20-8.12 (m, 1H), 7.56 (ddd, J=8.3, 7.1, 2.0 Hz, 1H), 7.45 (td, J=8.0,5.1 Hz, 0.5H), 7.28-7.22 (m, 1.5H), 7.21-7.08 (m, 1.5H), 7.05-6.96 (m,0.5H), 6.88 (dddd, J=13.2, 7.1, 5.1, 1.0 Hz, 1H), 6.71 (dt, J=8.4, 0.9Hz, 0.5H), 6.61 (dt, J=8.4, 0.9 Hz, 0.5H), 4.70-4.61 (m, 1H), 4.15-4.07(m, 1H), 4.06-3.89 (m, 2H), 2.26 (ddt, J=15.3, 8.3, 4.5 Hz, 1H),1.93-1.27 (m, 6H).

Example 53(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-10 (266 mg, 1.2 mmol) in THF (4 mL) at 0 C was addedNaH (60 wt % in mineral oil, 70 mg, 1.8 mmol). After 15 min,3-chloropyridazine (160 mg, 1.4 mmol) was added. The reaction allowed towarm to rt. After 18 h, H₂O was added and the mixture extracted withEtOAc. The organic layer was dried. Purification via silica gelchromatography (0-30% EtOAc in heptane) gave the title compound (300 mg,90%). MS (ESI) mass calcd. for C₁₆H₂₃N₃O₃, 305.2; m/z found 306.0[M+H]⁺.

Step B: (±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptanehydrochloride. To the title compound from step A (300 mg, 1 mmol) in1,4-dioxane (3 mL) was added 6N HCl in iPrOH (1 mL). The reaction washeated to 70° C. for 3 h, cooled to rt and concentrated to give thetitle compound that was used without further purification. MS (ESI) masscalcd. for C₁₁H₁₅N₃O, 205.1; m/z found 206.0 [M+H]⁺.

Step C:(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.To 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (270 mg, 1.3 mmol)in DMF (3 mL) was added DIPEA (630 μL, 3.6 mmol), HBTU (590 mg, 1.5mmol) and the title compound from step B (250 mg, 1 mmol). Afterstirring overnight, saturated NaHCO₃ (aq) was added and the mixtureextracted with EtOAc (3×). The combined organics were dried (MgSO₄).Purification by reverse phase chromatography gave material that wastriturated with Et₂O/pentane to give the title compound (115 mg, 28%) asa beige solid. MS (ESI) mass calcd. for C₂₀H₂₁N₇O₂, 391.2; m/z found392.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.91 (dd, J=8.5, 4.4 Hz, 1H), 8.23-8.04(m, 3H), 7.69-7.52 (m, 1.5H), 7.41 (d, J=8.4 Hz, 0.5H), 7.28 (d, J=8.9Hz, 0.5H), 7.10 (d, J=8.9 Hz, 0.5H), 4.60 (t, J=4.8 Hz, 1H), 4.40-4.19(m, 2H), 3.87 (t, J=4.3 Hz, 0.5H), 3.79 (d, J=4.3 Hz, 0.5H), 2.58 (s,1.5H), 2.46-2.24 (m, 1H), 2.06 (s, 1.5H), 1.81-1.34 (m, 6H).

Example 54(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A:(±)-tert-butyl-2-(((methylsulfonyl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-10 (545 mg, 2.4 mmol) in DCM (12 mL) at 0° C. wasadded TEA (333 μL, 2.4 mmol) followed by MsCl (190 μL, 2.4 mmol). After2 h, brine was added and the mixture was extracted with DCM (2×). Thecombined organics were dried (Na₂SO₄) to give the title compound (650mg, 89%) that was used without further purification. MS (ESI) masscalcd. for C₁₂H₂₃NO₅S, 305.1; m/z found 249.9 [M−55]⁺.

Step B: (±)-tert-butyl2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To 2-methylpyridin-3-ol in DMF was added KOH. The solution was stirredfor 30 min at rt, then the title compound from step A was added and thereaction was heated at 80° C. After 5 h, H₂O was added and the mixtureextracted with EtOAc. The combined organic layers were dried (MgSO₄).Purification via silica gel chromatography (0-7% MeOH in DCM) gave thetitle compound (201 mg, 90%). MS (ESI) mass calcd. for C₁₈H₂₆N₂O₃,318.2; m/z found 319.0 [M+1]⁺.

Step C:(±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.Prepared analogous to example 53 step B substituting (±)-tert-butyl2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylatewith (±)-tert-butyl2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.MS (ESI) mass calcd. for C₁₃H₁₈N₂O, 218.1; m/z found 219.1 [M+1]⁺.

Step D:(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.

Prepared analogous to example 53 step C substituting(±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptanehydrochloride with(±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. MS(ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR(DMSO-D₆): 8.22-7.92 (m, 4H), 7.55 (d, J=8.4 Hz, 0.3H), 7.45-7.33 (m,1H), 7.32-7.10 (m, 1.7H), 4.60-4.57 (m, 1H), 3.92-3.67 (m, 3H), 2.57 (s,0.9H), 2.42-2.18 (m, 1.9H), 2.08 (s, 2.1H), 1.95 (s, 2.1H), 1.80-1.31(m, 6H).

Example 55(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((3-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to Example 7 Step A Method A substituting PBu₃ withPPh₃, DEAD with DIAD, 5-fluoropyridin-2(1H)-one with3-methylpyridin-2-ol and performing the reaction at rt. MS (ESI) masscalcd. for C₁₈H₂₆N₂O₃, 318.2; m/z found 319.0 [M+H]⁺.

Step B:(±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.Prepared analogous to Example 53 Step B substituting (±)-tert-butyl2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylatewith (±)-tert-butyl2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.MS (ESI) mass calcd. for C₁₃H₁₈N₂O, 218.1; m/z found 219.0 [M+H]⁺.

Step C:(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((3-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.

Prepared analogous to Example 53 Step C substituting(±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptanehydrochloride with(±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. MS(ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺.

Example 56(±)-(2-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Step A: (±)-tert-butyl2-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to Example 7 Step A Method A substituting THF withPhCH₃ and 5-fluoropyridin-2(1H)-one with 1-methyl-1H-pyrazol-5-ol. MS(ESI) mass calcd. for C₁₆H₂₅N₃O₃, 307.2; m/z found 308.0 [M+H]⁺.

Step B:(±)-2-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.Prepared analogous to Example 53 Step B substituting (±)-tert-butyl2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylatethe title compound of Step A. MS (ESI) mass calcd. for C₁₁H₁₇N₃O, 207.1;m/z found 208.0 [M+H]⁺.

Step C:(±)-(2-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone.Prepared analogous to Example 53 Step C substituting(±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptanehydrochloride with the title compound of Step B. MS (ESI) mass calcd.for C₂₀H₂₃N₇O₂, 393.2; m/z found 394.2 [M+H]⁺. ¹H NMR (DMSO-D₆):8.18-8.05 (m, 3H), 7.56 (d, J=8.4 Hz, 0.4H), 7.49 (d, J=8.4 Hz, 0.6H),7.23 (d, J=1.7 Hz, 0.4H), 7.19 (d, J=1.7 Hz, 0.6H), 5.70 (d, J=1.8 Hz,0.4H), 5.59 (d, J=1.8 Hz, 0.6H), 4.59-4.56 (m, 1H), 3.96-3.76 (m, 3H),3.57 (s, 1.2H), 3.34 (s, 1.8H), 2.58 (s, 1.2H), 2.39-2.17 (m, 2.8H),1.87-1.27 (m, 6H).

Example 57(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-4-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 54 substituting 2-methylpyridin-3-ol withpyridin-4-ol. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found391.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.41 (d, J=5.5 Hz, 0.8H), 8.36 (d, J=5.5Hz, 1.2H), 8.20-8.02 (m, 3H), 7.55 (d, J=8.4 Hz, 0.4H), 7.40 (d, J=8.4Hz, 0.6H), 7.00 (d, J=6.2 Hz, 0.8H), 6.88 (d, J=6.2 Hz, 1.2H), 4.64-4.51(m, 1H), 4.02-3.78 (m, 2.4H), 3.75 (d, J=4.4 Hz, 0.6H), 2.57 (s, 1.2H),2.39-2.20 (m, 1H), 2.04 (s, 1.8H), 1.87-1.30 (m, 6H).

Example 58 #(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 54 substituting 2-methylpyridin-3-ol withpyridin-3-ol. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found391.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.33 (d, J=2.7 Hz, 0.4H), 8.21-8.05 (m,4.6H), 7.55 (d, J=8.4 Hz, 0.4H), 7.46-7.25 (m, 2.6H), 4.58 (t, J=4.8 Hz,1H), 3.95-3.80 (m, 2.4H), 3.77 (d, J=4.4 Hz, 0.6H), 2.57 (s, 1.2H),2.38-2.18 (m, 1H), 2.02 (s, 1.8H), 1.85-1.31 (m, 6H).

Example 59(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyrimidin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 53 substituting 2-chloropyridazine with2-chloropyrimidine. MS (ESI) mass calcd. for C₂₀H₂₁N₇O₂, 391.2; m/zfound 392.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.65 (d, J=4.8 Hz, 0.8H), 8.59 (d,J=4.8 Hz, 1.2H), 8.22-8.02 (m, 3H), 7.56 (d, J=8.4 Hz, 0.4H), 7.44 (d,J=8.4 Hz, 0.6H), 7.19-7.13 (m, 1H), 4.59 (t, J=4.5 Hz, 0.6H), 4.55 (d,J=4.4 Hz, 0.4H), 4.24-4.04 (m, 2H), 3.85 (t, J=4.3 Hz, 0.4H), 3.78 (d,J=4.0 Hz, 0.6H), 2.58 (s, 1.2H), 2.39-2.21 (m, 1H), 2.11 (s, 1.8H),1.86-1.29 (m, 6H).

Example 60(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyrazin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 53 substituting 2-chloropyridazine with2-pyrazine. MS (ESI) mass calcd. for C₂₀H₂₁N₇O₂, 391.2; m/z found 392.2[M+H]⁺.

Example 61(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyrimidin-4-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 55 substituting 3-methylpyridin-2-ol withpyrimidin-4-ol. MS (ESI) mass calcd. for C₂₀H₂₁N₇O₂, 391.2; m/z found392.2 [M+H]⁺. The product is present as a mixture of conformers (ratioca. 50:50) ¹H NMR (300 MHz, DMSO) 8.84 (s, 0.5H), 8.77 (s, 0.5H), 8.53(d, J=5.8 Hz, 0.5H), 8.49 (d, J=5.8 Hz, 0.5H), 8.22-8.01 (m, 3H), 7.55(d, J=8.4 Hz, 0.5H), 7.43 (d, J=8.4 Hz, 0.5H), 7.00 (d, J=5.7 Hz, 0.5H),6.85 (d, J=5.8 Hz, 0.5H), 4.58 (t, J=3.7 Hz, 0.5H), 4.53 (d, J=4.2 Hz,0.5H), 4.25-4.04 (m, 2H), 3.85 (t, J=3.7 Hz, 0.5H), 3.75 (d, J=3.9 Hz,0.5H), 2.57 (s, 1.5H), 2.40-2.16 (m, 1H), 2.12 (s, 1.5H), 1.85-1.31 (m,6H).

Example 62(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 55 substituting 3-methylpyridin-2-ol with6-methylpyridin-2-ol. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/zfound 405.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.17 (d, J=8.4 Hz, 0.5H), 8.12 (d,J=8.4 Hz, 0.5H), 8.10 (s, 1H), 8.06 (s, 1H), 7.63-7.49 (m, 1.5H), 7.41(d, J=8.4 Hz, 0.5H), 6.85 (d, J=7.2 Hz, 0.5H), 6.81 (d, J=7.2 Hz, 0.5H),6.64 (d, J=8.2 Hz, 0.5H), 6.46 (d, J=8.2 Hz, 0.5H), 4.58 (t, J=4.4 Hz,0.5H), 4.54 (d, J=4.5 Hz, 0.5H), 4.16-3.95 (m, 2H), 3.83 (t, J=4.4 Hz,0.5H), 3.74 (d, J=4.4 Hz, 0.5H), 2.58 (s, 1.5H), 2.43 (s, 1.5H), 2.37(s, 1.5H), 2.33-2.14 (m, 1H), 2.11 (s, 1.5H), 1.85-1.31 (m, 6H).

Example 63(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(oxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 withintermediate A-43. MS (ESI) mass calcd. for C₂₂H₂₁FN₄O₃, 408.2; m/zfound 409.2 [M+H].

Example 64(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with6-methyl-3-(pyrimidin-2-yl)picolinic acid. MS (ESI) mass calcd. forC₂₃H₂₂FN₅O₂, 419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.91 (d,J=4.9 Hz, 0.8H), 8.84 (d, J=4.9 Hz, 1.2H), 8.33-8.29 (m, 1H), 8.22 (d,J=3.1 Hz, 0.4H), 8.13 (d, J=3.1 Hz, 0.6H), 7.76-7.59 (m, 1H), 7.53-7.41(m, 1.4H), 7.35 (d, J=8.1 Hz, 0.6H), 6.94 (dd, J=9.1, 3.6 Hz, 0.4H),6.75 (dd, J=9.1, 3.6 Hz, 0.6H), 4.59 (t, J=4.1 Hz, 0.6H), 4.56 (d, J=3.8Hz, 0.4H), 4.16 (dd, J=14.6, 6.2 Hz, 1H), 4.08-3.97 (m, 1H), 3.87 (br s,0.4H), 3.76 (d, J=3.9 Hz, 0.6H), 2.56 (s, 1.2H), 2.39-2.15 (m, 1H), 2.10(s, 1.8H), 1.91-1.32 (m, 6H).

Example 65(±)-(3,6′-dimethyl-[2,3′-bipyridin]-2′-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid. MS (ESI) mass calcd.for C₂₅H₂₅FN₄O₂, 432.2; m/z found 433.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.33(t, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79-7.60 (m, 3H), 7.40 (d, J=7.9 Hz,0.5H), 7.32-7.23 (m, 1H), 7.20 (dd, J=7.6, 4.8 Hz, 0.5H), 6.85 (dd,J=9.1, 3.6 Hz, 0.5H), 6.80 (dd, J=9.1, 3.6 Hz, 0.5H), 4.39 (brs, 0.5H),4.35 (d, J=4.1 Hz, 0.5H), 4.19 (t, J=10.3 Hz, 0.5H), 4.04 (dd, J=10.4,5.2 Hz, 0.5H), 3.90 (d, J=4.8 Hz, 0.5H), 3.85 (t, J=4.0 Hz, 0.5H),3.75-3.53 (m, 1H), 2.56 (s, 1.5H), 2.22 2.17 (m, 3.5H), 2.11 (s, 1.5H),1.90-1.81 (m, 0.5H), 1.79-1.17 (m, 6H).

Example 66(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with6-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)picolinic acid. MS (ESI) masscalcd. for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (DMSO-D₆):8.33 (d, J=8.1 Hz, 0.4H), 8.28 (d, J=8.1 Hz, 0.6H), 8.14 (d, J=3.1 Hz,0.4H), 8.10 (d, J=3.1 Hz, 0.6H), 7.76-7.60 (m, 1H), 7.58 (d, J=8.2 Hz,0.4H), 7.47 (d, J=8.2 Hz, 0.6H), 6.95 (dd, J=3.6, 9.2 Hz, 0.4H), 6.72(dd, J=3.6, 9.2 Hz, 0.6H), 4.67 (t, J=4.5 Hz, 0.6H), 4.62 (d, J=4.6 Hz,0.4H), 4.16-3.92 (m, 2H), 3.81 (t, J=4.3 Hz, 0.4H), 3.73 (d, J=4.6 Hz,0.6H), 2.60 (s, 1.2H), 2.41 (s, 1.2H), 2.38 (s, 1.8H), 2.37-2.19 (m,1H), 2.18 (s, 1.8H), 1.90-1.30 (m, 6H).

Example 67(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(3-methyl-1H-pyrazol-1-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with6-methyl-3-(3-methyl-1H-pyrazol-1-yl)picolinic acid. MS (ESI) masscalcd. for C₂₃H₂₄FN₅O₂, 421.2; m/z found 422.2 [M+H]⁺. MP=123.2° C.

Example 68(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrrolidin-1-yl)pyridin-2-yl)methanone

Step A: 6-methyl-3-(pyrrolidin-1-yl)picolinonitrile. To2-bromo-6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine (720 mg, 3.7 mmol),pyrrolidine (450 μL, 5.5 mmol), Pd(OAc)₂ (25 mg, 11 mol %), XPhos (122mg, 25 mol %) and Cs₂CO₃ (2.4 g, 7.3 mmol) in a sealed tube was addedPhCH₃. The vessel was sealed and heated at 100° C. overnight. Aftercooling to rt, the reaction was diluted with EtOAc and H₂O. The organiclayer was dried (MgSO₄) and concentrated. Purification via silica gelchromatography (0-50% EtOAc in DCM) gave the title compound (186 mg,27%).

Step B: 6-methyl-3-(pyrrolidin-1-yl)picolinic acid. To the titlecompound of Step A (162 mg, 0.9 mmol) in EtOH (2.6 mL) was added 4M KOH(650 μL, 2.6 mmol). The reaction was then heated at 90° C. for 18 h.Additional 4M KOH (1.5 mL, 6 mmol) was added and heating continuedovernight. The reaction was then cooled to rt, acidified with 1N HCl(aq), concentrated and used without further purification in the nextstep.

Step C:(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrrolidin-1-yl)pyridin-2-yl)methanonePrepared analogous to Example 7 substituting intermediate A-9 with thetitle compound from Step B. MS (ESI) mass calcd. for C₂₃H₂₇FN₄O₂, 410.2;m/z found 411.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.14 (d, J=3.0 Hz, 0.5H), 8.10(d, J=3.0 Hz, 0.5H), 7.68-7.38 (m, 2H), 6.92 (dd, J=9.1, 3.6 Hz, 0.5H),6.71 (dd, J=9.1, 3.6 Hz, 0.5H), 4.66 (br s, 0.5H), 4.60 (br s, 0.5H),4.08-3.01 (m, 7H), 2.45 (s, 1.5H), 2.40-2.01 (m, 2.5H), 1.94-1.30 (m,10H).

Example 69 #(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(3-methylisoxazol-5-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with6-methyl-3-(3-methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd.for C₂₃H₂₃FN₄O₃, 422.2; m/z found 423.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.11(dt, J=10.0, 5.4 Hz, 2H), 7.77-7.55 (m, 1H), 7.50 (d, J=8.2 Hz, 0.4H),7.38 (d, J=8.2 Hz, 0.6H), 6.94 (dd, J=9.1, 3.6 Hz, 0.4H), 6.70 (dd,J=9.1, 3.6 Hz, 0.6H), 6.62 (d, J=1.6 Hz, 1H), 4.67 (t, J=4.6 Hz, 0.6H),4.61 (d, J=4.7 Hz, 0.4H), 3.98-3.88 (m, 2H), 3.60 (t, J=4.5 Hz, 0.4H),3.54 (d, J=3.8 Hz, 0.6H), 2.55 (s, 1.2H), 2.38-2.14 (m, 4H), 2.12 (s,1.8H), 1.86-1.13 (m, 6H).

Example 70(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone

Prepared analogous to Example 63 substituting6-methyl-3-(oxazol-2-yl)picolinic acid with6-methyl-3-(1H-pyrazol-1-yl)picolinic acid. MS (ESI) mass calcd. forC₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.17 (d,J=3.1 Hz, 0.5H), 8.13 (d, J=3.1 Hz, 0.5H), 8.08 (t, J=2.4 Hz, 1H), 7.95(t, J=8.5 Hz, 1H), 7.74-7.61 (m, 2H), 7.49 (d, J=8.3 Hz, 0.5H), 7.36 (d,J=8.4 Hz, 0.5H), 6.91 (dd, J=9.1, 3.6 Hz, 0.5H), 6.72 (dd, J=9.1, 3.6Hz, 0.5H), 6.52-6.49 (m, 0.5H), 6.49-6.46 (m, 0.5H), 4.55 (t, J=4.5 Hz,0.5H), 4.50 (d, J=4.7 Hz, 0.5H), 3.94 (d, J=7.6 Hz, 2H), 3.67 (t, J=4.2Hz, 0.5H), 3.59 (d, J=4.5 Hz, 0.5H), 2.54 (s, 1.5H), 2.30-2.11 (m, 1H),2.07 (s, 1.5H), 1.76-1.14 (m, 6H).

Example 71(±)-(5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd.for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.0 [M+H]⁺. MP=159.7° C.

Example 72(±)-(4-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with4-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd.for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.0 [M+H]⁺. MP=114.5° C.

Example 73(±)-(3-(dimethylamino)-6-methylpyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 3-(dimethylamino)-6-methylpicolinamide. A mixture of3-bromo-6-methylpicolinonitrile (1 g, 5 mmol) and dimethylamine (2 mL)were heated in a microwave reactor for 2 h at 140° C. The mixture wasthen concentrated and purified via silica gel chromatography (0-5% MeOHin DCM) to give the title compound (249 mg, 27%). MS (ESI) mass calcd.for C₉H₁₃N₃O, 179.1; m/z found 180.0 [M+H].

Step B: 3-(dimethylamino)-6-methylpicolinic acid. To the title compoundof Step A (91 mg, 0.5 mmol) in EtOH (1 mL) was added 4M KOH (0.5 μL).The reaction was then heated at 90° C. for 18 h. The reaction was thencooled to rt, acidified with 1N HCl (aq) to pH=3, concentrated and usedwithout further purification in the next step.

Step C: Prepared analogous to Example 2 substituting intermediate A-9with the title compound of Step B. MS (ESI) mass calcd. for C₂₁H₂₆N₄O₂,366.2; m/z found 367 [M+H]⁺.

Example 74(±)-(3-(2H-1,2,3-triazol-2-yl)quinolin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylic acid. MS (ESI) masscalcd. for C₂₄H₂₂N₆O₂, 426.2; m/z found 427.2 [M+H]⁺. ¹H NMR (DMSO-D₆):8.93 (s, 0.5H), 8.87 (s, 0.5H), 8.26-8.09 (m, 2H), 7.96-7.86 (m, 0.5H),7.82-7.51 (m, 5H), 7.33 (d, J=8.4 Hz, 0.5H), 7.00 (t, J=6.0 Hz, 1H),6.87 (d, J=8.3 Hz, 0.5H), 6.52 (d, J=8.3 Hz, 0.5H), 4.70-4.57 (m, 1H),4.33 (t, J=10.5 Hz, 0.5H), 4.24-4.05 (m, 1.5H), 4.00 (br t, J=3.8 Hz,0.5H), 3.93 (d, J=3.6 Hz, 0.5H), 2.44-2.20 (m, 1H), 2.01-1.35 (m, 6H).

Example 75(±)-(7-ethoxyquinolin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 withintermediate A-29. MS (ESI) mass calcd. for C₂₄H₂₅N₃O₃, 403.2; m/z found404.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.02-8.54 (m, 1.6H), 8.42 (d, J=7.9 Hz,0.8H), 8.31-7.83 (m, 2.2H), 7.83-6.75 (m, 3.8H), 6.64-6.46 (m, 0.2H),6.24 (m, 0.4H), 4.86-4.62 (m, 1.2H), 4.46-4.01 (m, 3.6H), 3.61-3.23 (m,1.2H), 2.44-2.06 (m, 1H), 2.06-1.15 (m, 9H).

Example 76(±)-(3,6-dimethylimidazo[1,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 3,6-dimethylimidazo[1,2-a]pyridine-5-carboxylic acid. Preparedanalogous to Example 82 substituting chloroacetaldehyde with2-bromopropanal. MS (ESI) mass calcd. for C₁₀H₁₀N₂O₂, 190.1; m/z found191.0 [M+H]⁺.

Step B:(±)-(3,6-dimethylimidazo[1,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 2 substituting intermediate A-9 with thetitle compound of Step A. MS (ESI) mass calcd. for C₂₂H₂₄N₄O₂, 376.2;m/z found 377.2 [M+H]⁺. The product is present as a mixture ofconformers (ratio ca. 85:15). ¹H NMR (300 MHz, DMSO) 8.18 (dd, J=4.5,1.4 Hz, 0.85H), 7.91 (d, J=5.1 Hz, 0.15H), 7.74 (td, J=7.1, 1.8 Hz,0.85H), 7.53 (d, J=9.1 Hz, 0.85H), 7.50-7.39 (m, 0.15H), 7.36 (s, 1H),7.12 (dd, J=6.3 Hz, 1H), 7.06-6.95 (m, 0.85H), 6.88 (d, J=8.4 Hz,0.85H), 6.72 (d, J=8.6 Hz, 0.15H), 6.62 (d, J=7.4 Hz, 0.15H), 6.46 (d,J=8.5 Hz, 0.15H), 4.77 (d, J=4.4 Hz, 0.85H), 4.72 (d, J=3.6 Hz, 0.15H),4.25-4.10 (m, 1H), 4.10-3.98 (m, 1H), 3.78 (br s, 0.85H), 3.69 (br s,0.15H), 2.48-2.38 (m, 1.85H), 2.36 (s, 2H), 2.30 (s, 2H), 2.25-2.21 (m,0.85H), 2.20-2.16 (m, 0.3H), 1.98-1.32 (m, 6H).

Example 77(±)-(1-methyl-4-phenyl-1H-pyrazol-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with1-methyl-4-phenyl-1H-pyrazole-3-carboxylic acid. MS (ESI) mass calcd.for C₂₃H₂₄N₄O₂, 388.2; m/z found 389.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.18(d, J=3.8 Hz, 0.5H), 8.08 (d, J=3.9 Hz, 0.5H), 8.03 (s, 0.5H), 7.92 (s,0.5H), 7.76-7.62 (m, 1H), 7.46-7.16 (m, 5H), 7.04-6.90 (m, 1H), 6.84 (d,J=8.3 Hz, 0.5H), 6.71 (d, J=8.3 Hz, 0.5H), 4.60 (t, J=4.6 Hz, 0.5H),4.56 (d, J=4.7 Hz, 0.5H), 4.15 (br s, 1H), 4.06 (br s, 1H), 3.98-3.83(m, 2.5H), 3.55 (s, 1.5H), 2.29-2.15 (m, 1H), 1.79-1.22 (m, 6H).

Example 78(±)-(1-methyl-3-phenyl-1H-pyrazol-4-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with1-methyl-3-phenyl-1H-pyrazole-4-carboxylic acid. MS (ESI) mass calcd.for C₂₃H₂₄N₄O₂, 388.2; m/z found 389.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.16(br s, 1H), 8.09-7.75 (m, 1H), 7.70 (t, J=7.2 Hz, 1H), 7.58 (d, J=7.0Hz, 2H), 7.47-7.20 (m, 3H), 7.10-6.90 (m, 1H), 6.92-6.52 (br s, 1H),4.48 (br s, 1H), 4.21-3.44 (m, 6H), 2.17 (br s, 1H), 1.86-1.05 (m, 6H).

Example 79(±)-((3,7-dimethylimidazo[1,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: Prepared analogous to Example 76 substituting6-amino-3-methylpicolinic acid with 2-amino-4-methylnicotinic acid.

Step B:(±)-((3,7-dimethylimidazo[1,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 2 substituting intermediate A-9 with3,7-dimethylimidazo[1,2-a]pyridine-8-carboxylic acid. MS (ESI) masscalcd. for C₂₂H₂₄N₄O₂, 376.2; m/z found 377.2 [M+H]⁺. ¹H NMR (DMSO-D₆):8.24-8.03 (m, 2H), 7.80-7.68 (m, 0.5H), 7.61 (br s, 0.5H), 7.30 (s, 1H),7.06-6.27 (m, 3H), 4.70 (t, J=4.3 Hz, 1H), 4.32-3.67 (m, 2H), 3.42 (m,2H), 2.45 (s, 2H), 2.38-2.02 (m, 4H), 2.02-1.18 (m, 6H).

Example 80(±)-(7-methylimidazo[1,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 7-methylimidazo[1,2-a]pyridine-8-carboxylic acid. Preparedanalogous to Example 82 substituting 6-amino-3-methylpicolinic acid with2-amino-4-methylnicotinic acid.

Step B:(±)-(7-methylimidazo[1,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanonePrepared analogous to Example 2 substituting intermediate A-9 with thetitle compound of Step A. MS (ESI) mass calcd. for C₂₁H₂₂N₄O₂, 362.2;m/z found 363.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.46 (d, J=6.9 Hz, 0.5H), 8.38(d, J=6.3 Hz, 0.5H), 8.17 (d, J=3.6 Hz, 0.5H), 8.12 (d, J=3.8 Hz, 0.5H),7.91 (s, 1H), 7.79-7.39 (m, 2H), 7.14-6.70 (m, 2H), 6.70-6.33 (m, 1H),4.71 (br s, 1H), 4.45-3.66 (m, 2H), 3.63-3.22 (m, 2H), 2.44-2.02 (m,3H), 2.02-1.08 (m, 6H).

Example 81(±)-(1-methyl-4-phenyl-1H-pyrazol-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with1-methyl-4-phenyl-1H-pyrazole-5-carboxylic acid. MS (ESI) mass calcd.for C₂₃H₂₄N₄O₂, 388.2; m/z found 389.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.19(d, J=3.8 Hz, 0.6H), 8.09 (d, J=4.0 Hz, 0.4H), 7.79-7.57 (m, 2H),7.43-7.19 (m, 5H), 7.05-6.91 (m, 1H), 6.84 (d, J=8.3 Hz, 0.6H), 6.62 (d,J=8.3 Hz, 0.4H), 4.62 (t, J=4.5 Hz, 0.4H), 4.57 (d, J=4.5 Hz, 0.6H),3.96-3.87 (m, 2H), 3.85 (s, 1.8H), 3.79 (s, 1.2H), 3.58 (t, J=4.3 Hz,0.6H), 3.52 (d, J=4.7 Hz, 0.4H), 2.28-2.02 (m, 1H), 1.76-1.07 (m, 6H).

Example 82(±)-((6-methylimidazo[1,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 6-amino-3-methylpicolinic acid. To methyl6-amino-3-bromopicolinate (500 mg, 2.2 mmol), tetramethylstannane (900μL, 6.5 mmol) and LiCl (354 mg, 8.7 mmol) in DMF (6 mL) was addedPd(PPh₃)₄ (76 mg, 10 mol %). The reaction mixture was heated at 110° C.for 3 h. Additional tetramethylstannane, LiCl and Pd(PPh₃)₄ were addedand heating continued for 6 h. Purification via silica gelchromatography (0-20% MeOH in DCM) gave the title compound.

Step B: 6-methylimidazo[1,2-a]pyridine-5-carboxylic acid. To the titlecompound of Step A (340 mg, 2.2 mmol) in H₂O (7 mL) was added 1M aq.NaOH (2.2 mL, 2.2 mmol) and chloroacetaldehyde (210 μL, 3.4 mmol) andthe reaction mixture heated in a microwave reactor at 150° C. for 2 h.Additional 1M aq. NaOH (2.2 mL, 2.2 mmol) and chloroacetaldehyde (210μL, 3.4 mmol) were added and heating continued at 150° C. for 2 h. Thereaction was purified via prep HPLC to give the title compound (282 mg,72%). MS (ESI) mass calcd. for C₉H₈N₂O₂, 176.1; m/z found 177.0 [M+H]⁺.

Step C:(±)-((6-methylimidazo[1,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 2 substituting intermediate A-9 with6-methylimidazo[1,2-a]pyridine-5-carboxylic acid. The product is presentas a mixture of conformers (ratio ca. 80:20) ¹H NMR (300 MHz, DMSO)8.44-8.13 (m, 1.6H), 8.13-7.86 (m, 3H), 7.86-7.41 (m, 1.2H), 6.97 (br d,J=33.5 Hz, 1.6H), 6.68 (br d, J=1.0 Hz, 0.2H), 6.39 (br d, J=1.0 Hz,0.4H), 4.80 (d, J=16.5 Hz, 1.6H), 4.09-4.06 (m, 0.2H), 3.58 (s, 2H),3.46-3.30 (m, 0.2H), 2.47-2.07 (m, 4H), 2.07-1.02 (m, 6H).

Example 83(±)-(3-ethoxyisoquinolin-4-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 164 substituting intermediate B-9 withintermediate B-10. MS (ESI) mass calcd. for C₂₄H₂₅N₃O₃, 403.2; m/z found404.2 [M+H]⁺.

Example 84(±)-(1-methyl-5-phenyl-1H-pyrazol-4-yl)(-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 withintermediate A-51. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₂, 388.2; m/z found389.2 [M+H]⁺.

Example 85(±)-(6-methyl-3-(4-methylpiperazin-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 6-methyl-3-(4-methylpiperazin-1-yl)picolinonitrile. Preparedanalogous to Example 68 substituting pyrrolidine with1-methylpiperazine. MS (ESI) mass calcd. for C₁₂H₁₆N4, 216.1; m/z found217.0 [M+H]⁺.

Step B: 6-methyl-3-(4-methylpiperazin-1-yl)picolinic acid. Preparedanalogous to Example 68 substituting6-methyl-3-(pyrrolidin-1-yl)picolinonitrile with the title compound ofStep A. MS (ESI) mass calcd. for C₁₂H₁₇N₃O₂, 235.1; m/z found 236.0[M+H]⁺.

Step C: Prepared analogous to Example 2 substituting intermediate A-9with the title compound of Step B. MS (ESI) mass calcd. for C₂₄H₃₁N₅O₂,421.2; m/z found 422.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.19-8.14 (m, 0.5H),8.12 (dd, J=5.0, 1.5 Hz, 0.5H), 7.78-7.68 (m, 0.5H), 7.68-7.59 (m,0.5H), 7.52 (d, J=8.4 Hz, 0.5H), 7.37 (d, J=8.4 Hz, 0.5H), 7.23 (d,J=8.4 Hz, 0.5H), 7.07 (d, J=8.3 Hz, 0.5H), 6.97 (ddd, J=12.3, 6.7, 5.4Hz, 1H), 6.87 (d, J=8.3 Hz, 0.5H), 6.59 (d, J=8.3 Hz, 0.5H), 4.63 (t,J=4.5 Hz, 0.5H), 4.59 (d, J=3.9 Hz, 0.5H), 4.19-3.81 (m, 2H), 3.46 (t,J=3.9 Hz, 0.5H), 3.39 (d, J=4.7 Hz, 0.5H), 3.07-2.92 (m, 2H), 2.92-2.78(m, 2H), 2.46-2.27 (m, 6H), 2.22-2.05 (m, 3.5H), 1.97 (s, 1.5H),1.94-1.27 (m, 6H).

Example 86(±)-(6-methyl-3-(piperazin-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: tert-butyl4-(2-cyano-6-methylpyridin-3-yl)piperazine-1-carboxylate. Preparedanalogous to Example 68 substituting pyrrolidine with tert-butylpiperazine-1-carboxylate. MS (ESI) mass calcd. for C₁₆H₂₂N₄O₂, 302.2;m/z found 303.0 [M+H]⁺.

Step B: 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpicolinicacid.

Prepared analogous to Example 68 substituting6-methyl-3-(pyrrolidin-1-yl)picolinonitrile with the title compound ofStep A. MS (ESI) mass calcd. for C₁₆H₂₃N₃O₄, 321.2; m/z found 322.0[M+H]⁺.

Step C: tert-butyl4-(6-methyl-2-((±)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carbonyl)pyridin-3-yl)piperazine-1-carboxylate.Prepared analogous to example 2 substituting intermediate A-9 with thetitle compound of Step B.

Step D:(±)-(6-methyl-3-(piperazin-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.To the title compound from step C (182 mg, 0.4 mmol) in 1,4-dioxane (1mL) was added 6N HCl in iPrOH (400 μL). The reaction was heated to 70°C. for 3 h, cooled to rt, concentrated and purified via reverse phasechromatography. The mixture was dissolved with a saturated NaHCO3 (aq)and extracted with DCM (×3). The organic layers were dried over MgSO4and concentrated. The crude product was triturated with diethyl etherand n-pentane to give the title compound (5 mg, 3%). MS (ESI) masscalcd. for C₂₃H₂₉N₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (DMSO-D₆):8.17 (d, J=4.0 Hz, 0.4H), 8.12 (d, J=3.8 Hz, 0.6H), 7.72 (t, J=7.6 Hz,0.4H), 7.63 (t, J=6.9 Hz, 0.6H), 7.48 (d, J=8.3 Hz, 0.4H), 7.34 (d,J=8.3 Hz, 0.6H), 7.22 (d, J=8.3 Hz, 0.4H), 7.06 (d, J=8.3 Hz, 0.6H),7.02-6.90 (m, 1H), 6.86 (d, J=8.1 Hz, 0.4H), 6.58 (d, J=8.3 Hz, 0.6H),4.63-4.60 (m, 1H), 4.14-3.92 (m, 2H), 3.86 (t, J=10.4 Hz, 1H), 2.99-2.65(m, 8H), 2.39 (s, 1H), 2.34-2.28 (m, 1H), 2.18-2.11 (m, 1H), 1.96-1.88(m, 2H), 1.86-1.20 (m, 6H).

Example 87(±)-(6-methyl-3-morpholinopyridin-2-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 6-methyl-3-morpholinopicolinonitrile. Prepared analogous toExample 68 substituting pyrrolidine with morpholine. MS (ESI) masscalcd. for C₁₁H₁₃N₃O, 203.1; m/z found 204.0 [M+H]⁺.

Step B: 6-methyl-3-morpholinopicolinic acid. Prepared analogous toExample 68 substituting 6-methyl-3-(pyrrolidin-1-yl)picolinonitrile withthe title compound of Step A. MS (ESI) mass calcd. for C₁₁H₁₄N₂O₃,222.1; m/z found 223.0 [M+H]⁺.

Step C: Prepared analogous to Example 2 substituting intermediate A-9with the title compound of Step B. MS (ESI) mass calcd. for C₂₃H₂₈N₄O₃,408.2; m/z found 409.2 [M+H]⁺.

Example 88(±)-(7-methoxyquinolin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 7-methoxyquinoline-8-carboxylic acid. In 1 g separate batches amixture of 2-amino-6-methoxybenzoic acid (1 g, 66 mmol) and acrolein(4.8 mL, 72 mmol) in 1,4-dioxane (66 mL) was heated in a microwavereactor for 20 min at 200° C. After combining the reactions, the mixturewas concentrated and purified via silica gel chromatography (0-10% MeOHin DCM) to give the title compound (2.8 g, 20%). MS (ESI) mass calcd.for C₁₁H₁₉NO₃, 203.1; m/z found 204.0 [M+H]⁺.

Step B: Prepared analogous to Example 2 substituting intermediate A-9with the title compound of Step A. MS (ESI) mass calcd. for C₂₃H₂₃N₃O₃,389.2; m/z found 390.2 [M+H]⁺.

Example 89(±)-(2-ethoxynaphthalen-1-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with2-ethoxy-1-naphthoic acid. MS (ESI) mass calcd. for C₂₅H₂₆N₂O₃, 402.2;m/z found 403.2 [M+H]⁺.

Example 90(±)-(3,6′-dimethyl-[2,3′-bipyridin]-2′-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid. MS (ESI) mass calcd.for C₂₅H₂₆N₄O₂, 414.2; m/z found 415.2 [M+H]⁺.

Example 91(±)-(3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd. forC₂₀H₂₀N₆O₂, 376.2; m/z found 377.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.70 (d,J=3.6 Hz, 0.5H), 8.40-7.99 (m, 4.5H), 7.82-7.47 (m, 2H), 7.02-6.85 (m,1H), 6.86 (d, J=8.2 Hz, 0.6H), 6.64 (d, J=8.1 Hz, 0.4H), 4.62-4.65 (m,1H), 4.20-3.97 (m, 3H), 2.35-2.24 (m, 1H), 2.00-1.09 (m, 6H).

Example 92(±)-(2-methyl-5-phenylthiazol-4-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with2-methyl-5-phenylthiazole-4-carboxylic acid. MS (ESI) mass calcd. forC₂₃H₂₃N₃O₂S, 405.2; m/z found 406.2 [M+H]⁺. ¹H NMR (DMSO-D₆) 8.18 (dd,J=5.0, 1.4 Hz, 0.5H), 8.10 (dd, J=5.0, 1.4 Hz, 0.5H), 7.77-7.61 (m, 1H),7.52-7.29 (m, 5H), 7.04-6.89 (m, 1H), 6.82 (d, J=8.3 Hz, 0.5H), 6.69 (d,J=8.3 Hz, 0.5H), 4.57 (t, J=4.5 Hz, 0.5H), 4.52 (d, J=4.7 Hz, 0.5H),3.90-3.79 (m, 2.5H), 3.69 (t, J=10.6 Hz, 0.5H), 2.69 (s, 1.5H), 2.28 (s,1.5H), 2.25-2.06 (m, 1H), 1.72-1.04 (m, 6H).

Example 93(±)-(6-methyl-3-(oxazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 withintermediate A-43. MS (ESI) mass calcd. for C₂₂H₂₂N₄O₃, 390.2; m/z found391.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.22 (dt, J=14.0, 7.8 Hz, 2.5H), 8.12(dd, J=5.0, 1.4 Hz, 0.5H), 7.78-7.68 (m, 0.5H), 7.68-7.59 (m, 0.5H),7.49 (d, J=8.2 Hz, 0.5H), 7.41-7.29 (n, 1.5H), 6.97 (ddd, J=14.7, 6.5,5.2 Hz, 1H), 6.87 (d, J=8.4 Hz, 0.5H), 6.63 (d, J=8.3 Hz, 0.5H), 4.66(t, J=4.6 Hz, 0.5H), 4.62 (d, J=4.8 Hz, 0.5H), 4.22-3.93 (m, 2H), 3.70(t, J=4.4 Hz, 0.5H), 3.61 (d, J=4.0 Hz, 0.5H), 2.55 (s, 1.5H), 2.40-2.14(m, 1H), 2.08 (s, 1.5H), 1.93-1.23 (m, 6H).

Example 94(±)-(6-methyl-3-(3-methylisoxazol-5-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with6-methyl-3-(3-methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd.for C₂₃H₂₄N₄O₃, 404.2; m/z found 405.0 [M+H]⁺. ¹H NMR (DMSO-D₆):8.20-8.02 (m, 2H), 7.73 (t, J=6.9 Hz, 0.4H), 7.65 (t, J=7.7 Hz, 0.6H),7.50 (d, J=8.1 Hz, 0.4H), 7.37 (d, J=8.2 Hz, 0.6H), 7.03-6.91 (m, 1H),6.87 (d, J=8.3 Hz, 0.4H), 6.68-6.58 (m, 1.6H), 4.68 (t, J=4.6 Hz, 0.6H),4.62 (d, J=4.7 Hz, 0.4H), 4.01-3.93 (m, 2H), 3.60 (t, J=4.4, 0.4H), 3.55(d, J=3.1, 0.6H), 2.55 (s, 1.2H), 2.36-2.14 (m, 4H), 2.09 (s, 1.8H),1.88-1.07 (m, 6H).

Example 95(±)-(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with6-methyl-3-(1H-pyrazol-1-yl)picolinic acid. ¹H NMR (DMSO-D₆): 8.19 (dd,J=5.0, 1.4 Hz, 0.5H), 8.14 (dd, J=5.1, 1.5 Hz, 0.5H), 8.08 (t, J=2.9 Hz,1H), 7.97 (d, J=8.3 Hz, 0.5H), 7.93 (d, J=8.3 Hz, 0.5H), 7.76-7.61 (m,2H), 7.49 (d, J=8.4 Hz, 0.5H), 7.34 (d, J=8.4 Hz, 0.5H), 6.97 (td,J=7.3, 5.2 Hz, 1H), 6.84 (d, J=8.3 Hz, 0.5H), 6.65 (d, J=8.3 Hz, 0.5H),6.53-6.48 (m, 0.5H), 6.48-6.43 (m, 0.5H), 4.55 (t, J=4.5 Hz, 0.5H), 4.51(d, J=4.7 Hz, 0.5H), 4.02-3.93 (m, 2H), 3.67 (t, J=4.1 Hz, 0.5H), 3.60(d, J=4.5 Hz, 0.5H), 2.54 (s, 1.5H), 2.31-2.11 (m, 1H), 2.04 (s, 1.5H),1.75-1.16 (m, 6H).

Example 96(±)-(6-methyl-3-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with6-methyl-3-(4-methyl-1H-pyrazol-1-yl)picolinic acid. MS (ESI) masscalcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺.

Example 97(±)-(6-methyl-3-(pyrrolidin-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with6-methyl-3-(pyrrolidin-1-yl)picolinic acid (Example 68). MS (ESI) masscalcd. for C₂₃H₂₈N₄O₂, 392.2; m/z found 393.2 [M+H]⁺. The product ispresent as a mixture of conformers (ratio ca. 50:50). ¹H NMR (300 MHz,DMSO) 8.14 (dd, J=5.1, 1.4 Hz, 0.5H), 8.11 (dd, J=5.1, 1.4 Hz, 0.5H),7.76-7.59 (m, 1H), 7.06 (q, J=8.6 Hz, 1H), 7.01-6.90 (m, 2H), 6.85 (d,J=8.3 Hz, 0.5H), 6.69 (d, J=8.3 Hz, 0.5H), 4.61 (t, J=4.6 Hz, 0.5H),4.58 (d, J=4.7 Hz, 0.5H), 4.19-3.91 (m, 2.5H), 3.88 (d, J=4.6 Hz, 0.5H),3.28-3.11 (m, 3H), 3.10-2.98 (m, 1H), 2.41-2.18 (m, 2.5H), 2.06 (s,1.5H), 1.95-1.28 (m, 10H).

Example 98(±)-(3,6′-dimethyl-[2,3′-bipyridin]-2′-yl)(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-10 (500 mg, 2.2 mmol) in THF (11 mL) at 0° C. wasadded NaH (176 mg, 60 wt % in mineral oil, 4.4 mmol). After 15 min,2-chloro-5-fluoropyrimidine (0.3 mL, 2.4 mmol) was added dropwise andthe 0° C. ice bath was removed. After 12 h, H₂O was added and thereaction extracted with EtOAc. The combined organics dried (Na₂SO₄).Purification via silica gel chromatography (5-30% EtOAc in heptane) gavethe title compound (490 mg, 69%) as a white solid. MS (ESI) mass calcd.for C₁₆H₂₂F₃N₃O₃, 323.4; m/z found 224.1 [M−100]⁺.

Step B:(±)-2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane.To the title compound from step A (474 mg, 1.5 mmol) in 1,4-dioxane (1.5mL) was added 6N HCl in iPrOH (1.5 mL). The reaction was heated to 40°C. for 1.5 h and concentrated to give the title compound that was usedwithout further purification in subsequent steps. MS (ESI) mass calcd.for C₁₁H₁₄FN₃O, 223.1; m/z found 224.0 [M+H]⁺.

Step C:(±)-(3,6′-dimethyl-[2,3′-bipyridin]-2′-yl)(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to example 2 substituting intermediate A-9 with3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid and intermediate B-10with the title compound of Step B. MS (ESI) mass calcd. for C₂₄H₂₄FN₅O₂,433.2; m/z found 434.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.71 (s, 2H), 8.32 (t,J=4.5 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.66 (t, J=7.3 Hz, 1H), 7.40 (d,J=7.9 Hz, 0.5H), 7.33-7.14 (m, 1.5H), 4.39 (br s, 0.5H), 4.34 (d, J=4.0Hz, 0.5H), 4.27 (t, J=10.4 Hz, 0.5H), 4.10 (dd, J=5.2, 1.0 Hz, 0.5H),3.90 (d, J=4.8 Hz, 0.5H), 3.85 (t, J=3.1 Hz, 0.5H), 3.69 (d, J=7.9 Hz,1H), 2.55 (s, 1.5H), 2.31-2.20 (m, 0.5H), 2.18 (s, 1.5H), 2.16 (s,1.5H), 2.12 (s, 1.5H), 2.01-1.82 (m, 0.5H), 1.81-1.14 (m, 6H).

Example 99(±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(3-methylisoxazol-5-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with6-methyl-3-(3-methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd.for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.71(s, 1H), 8.66 (s, 1H), 8.12 (d, J=8.1 Hz, 0.4H), 8.09 (d, J=8.2 Hz,0.6H), 7.50 (d, J=8.2 Hz, 0.4H), 7.40 (d, J=8.2 Hz, 0.6H), 6.64-6.63 (m,1H), 4.68 (t, J=4.6 Hz, 0.6H), 4.60 (d, J=4.7 Hz, 0.4H), 4.11-3.90 (m,2H), 3.62 (t, J=4.2 Hz, 0.4H), 3.55 (d, J=4.1 Hz, 0.5H), 2.55 (s, 1.2H),2.40-2.15 (m, 4H), 2.16 (s, 1.8H), 1.88-1.12 (m, 6H).

Example 100(±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(oxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with intermediateA-43. MS (ESI) mass calcd. for C₂₁H₂₀FN₅O₃, 409.2; m/z found 410.2[M+H]⁺. ¹H NMR (DMSO-D₆): 8.74 (s, 0.8H), 8.66 (s, 1.2H), 8.31-8.16 (m,2H), 7.50 (d, J=8.2 Hz, 0.4H), 7.38 (t, J=8.9 Hz, 1.6H), 4.67 (t, J=4.5Hz, 0.6H), 4.62 (d, J=4.7 Hz, 0.4H), 4.23 (t, J=10.1 Hz, 0.4H), 4.07(dt, J=10.0, 6.2 Hz, 1.6H), 3.72 (t, J=4.2 Hz, 0.4H), 3.62 (d, J=4.4 Hz,0.6H), 2.56 (s, 1.2H), 2.43-2.19 (m, 1H), 2.16 (s, 1.8H), 1.93-1.23 (m,6H).

Example 101(±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrrolidin-1-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with6-methyl-3-(pyrrolidin-1-yl)picolinic acid (example 68). MP=130° C.

Example 102(±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with intermediateA-9. MS (ESI) mass calcd. for C₂₂H₂₁FN₆O₂, 420.2; m/z found 421.2[M+H]⁺. ¹H NMR (DMSO-D₆): 8.93 (d, J=4.9 Hz, 0.8H), 8.88 (d, J=4.9 Hz,1.2H), 8.79 (s, 0.8H), 8.72 (s, 1.2H), 8.37-8.33 (m, 1H), 7.55-7.47 (m,1.2H), 7.40 (d, J=8.1 Hz, 0.6H), 4.67-4.61 (br s, 0.6H), 4.59 (d, J=4.0Hz, 0.4H), 4.33-4.22 (m, 1H), 4.18-4.07 (m, 1H), 3.91 (br s, 0.4H), 3.81(d, J=3.4 Hz, 0.6H), 2.59 (s, 1.4H), 2.48-2.25 (m, 1H), 2.15 (s, 1.8H),1.93-1.34 (m, 6H).

Example 103(±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with6-methyl-3-(4-methyl-1H-pyrazol-1-yl)picolinic acid. MP=151.2° C. ¹H NMR(DMSO-D₆): 8.73 (s, 1H), 8.69 (s, 1H), 7.92 (d, J=5.0 Hz, 0.5H), 7.90(d, J=5.0 Hz, 0.5H), 7.85 (d, J=2.3 Hz, 1H), 7.51-7.54 (m, 1.5H), 7.35(d, J=8.4 Hz, 0.5H), 4.57 (t, J=4.5 Hz, 0.5H), 4.51 (d, J=4.7 Hz, 0.5H),4.08-3.90 (m, 2H), 3.66 (t, J=4.0 Hz, 0.5H), 3.60 (d, J=4.0 Hz, 0.5H),2.53 (s, 1.5H), 2.35-2.14 (m, 1H), 2.10 (s, 1.5H), 2.07 (s, 1.5H), 2.04(s, 1.5H), 1.77-1.14 (m, 6H).

Example 104(±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with6-methyl-3-(1H-pyrazol-1-yl)picolinic acid. MS (ESI) mass calcd. forC₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺. MP-119.2° C.

Example 105(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 7 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. (ESI) mass calcd. forC₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.08-7.96 (m,1H), 7.88 (s, 2H), 7.81-7.73 (m, 1H), 7.56-7.12 (m, 3H), 6.85-6.62 (m,1H), 4.70-4.67 (m, 1H), 4.25-3.74 (m, 3H), 2.51-1.97 (m, 4H), 1.96-1.31(m, 6H).

Example 106(±)-(2,6-dimethoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2,6-dimethoxybenzoicacid. MS (ESI) mass calcd. for C₂₁H₂₃FN₂O₄, 386.2; m/z found 386.9[M+H]⁺. ¹H NMR (MeOD): 8.02-7.93 (m, 1H), 7.57-7.40 (m, 1H), 7.39-7.21(m, 1H), 6.87-6.63 (m, 2H), 6.62-6.38 (m, 1H), 4.83-4.65 (m, 1H),4.49-4.07 (m, 1H), 4.07-3.52 (m, 8H), 2.48-2.09 (m, 1H), 2.06-1.07 (m,6H).

Example 107(±)-((3-fluoro-2-methoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₂₀F₂N₂O₃,374.1; m/z found 375.1 [M+H]⁺. ¹H NMR (MeOD): 8.01-7.90 (m, 1H),7.56-7.38 (m, 1H), 7.28-7.06 (m, 2H), 7.02-6.53 (m, 2H), 4.82-4.66 (m,1H), 4.50-3.73 (m, 6H), 2.85-2.22 (m, 1H), 2.21-1.10 (m, 6H).

Example 108(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-methoxy-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with2-methoxy-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd.for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-7.74(m, 3H), 7.66-7.41 (m, 3H), 7.25-6.88 (m, 1H), 6.88-6.43 (m, 1H),4.78-4.64 (m, 1H), 4.51-3.57 (m, 6H), 2.48-0.94 (m, 7H).

Example 109(±)-(5-fluoro-2-(1H-pyrazol-5-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with5-fluoro-2-(1H-pyrazol-5-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₀F₂N₄O₂, 410.2; m/z found 411.2 [M+H]⁺. ¹H NMR (MeOD): 8.11-7.90(m, 1H), 7.80-7.59 (m, 2H), 7.58-7.40 (m, 1H), 7.36-6.94 (m, 2H),6.88-6.47 (m, 2H), 4.78-4.58 (m, 1H), 4.41-3.47 (m, 3H), 2.69-0.60 (m,8H).

Example 110(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with2-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.11-7.62 (m,4H), 7.59-6.48 (m, 4H), 4.78-4.68 (m, 1H), 4.50-3.37 (m, 3H), 2.80-0.82(m, 10H).

Example 111(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd.for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺. ¹H NMR (MeOD): 8.28-8.19(m, 1H), 8.06-7.88 (m, 3H), 7.57-7.35 (m, 2H), 6.89-6.60 (m, 1H),4.76-4.73 (m, 1H), 4.32-4.02 (m, 2H), 3.93-3.80 (m, 1H), 2.70-2.20 (m,4H), 2.05-1.42 (m, 6H).

Example 112(±)-(5-chloro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with sodium5-chloro-3-(2H-1,2,3-triazol-2-yl)picolinate. MS (ESI) mass calcd. forC₂₀H₁₈ClFN₆O₂, 428.1; m/z found 429.1 [M+H]⁺. ¹H NMR (MeOD): 8.74-8.17(m, 4H), 8.13-7.96 (m, 2H), 7.59-7.46 (m, 1H), 4.90-4.18 (m, 3H), 3.99(s, 1H), 2.98-2.39 (m, 1H), 2.10-1.19 (m, 6H).

Example 113(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with sodium5-methoxy-3-(2H-1,2,3-triazol-2-yl)picolinate. MS (ESI) mass calcd. forC₂₁H₂₁FN₆O₃, 424.2; m/z found 425.1 [M+H]⁺. ¹H NMR (MeOD): 8.37-7.79 (m,5H), 7.56-7.40 (m, 1H), 6.87-6.59 (m, 1H), 4.73 (s, 1H), 4.30-3.82 (m,6H), 2.48-2.11 (m, 1H), 2.07-1.42 (m, 6H).

Example 114(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with sodium5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoate. MS (ESI) mass calcd. forC₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (MeOD): 8.18-7.68 (m,4H), 7.58-7.38 (m, 1H), 7.24-6.85 (m, 2H), 6.85-6.57 (m, 1H), 4.78-4.55(m, 1H), 4.23-3.40 (m, 6H), 2.77-2.18 (m, 1H), 2.13-1.11 (m, 6H).

Example 115(±)-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₁H₁₉F₂N₅O₂, 411.2; m/z found 412.2 [M+H]⁺. ¹H NMR (MeOD): 8.11-7.71(m, 4H), 7.69-7.24 (m, 3H), 6.98-6.43 (m, 1H), 4.83-4.67 (m, 1H),4.53-3.34 (m, 3H), 2.50-0.96 (m, 7H).

Example 116(±)-(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₁H₁₉F₂N₅O₂, 411.2; m/z found 412.2 [M+H]⁺. ¹H NMR (MeOD): 8.11-7.71(m, 4H), 7.69-7.24 (m, 3H), 6.98-6.43 (m, 1H), 4.83-4.67 (m, 1H),4.53-3.34 (m, 3H), 2.50-0.96 (m, 7H).

Example 117(±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₁H₁₉F₂N₅O₂, 411.2; m/z found 412.2 [M+H]⁺. ¹H NMR (MeOD): 8.14-7.85(m, 3H), 7.70-7.18 (m, 4H), 6.81-6.65 (m, 1H), 4.67-4.32 (m, 1H),4.24-3.79 (m, 3H), 2.42-2.24 (m, 1H), 1.97-1.32 (m, 6H).

Example 118(±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with3-ethoxy-6-methylpicolinic acid. MS (ESI) mass calcd. for C₂₁H₂₄FN₃O₃,385.2; m/z found 385.9 [M+H]⁺. ¹H NMR (MeOD): 8.23-7.90 (m, 1H),7.57-7.11 (m, 3H), 6.87-6.53 (m, 1H), 4.85-4.69 (m, 1H), 4.51-3.56 (m,5H), 2.84-2.09 (m, 4H), 2.06-1.49 (m, 5H), 1.47-1.05 (m, 4H).

Example 119(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd.for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (MeOD): 8.12-7.81(m, 3H), 7.58-7.22 (m, 3H), 7.15-6.57 (m, 2H), 4.75-4.58 (m, 1H),4.48-3.74 (m, 6H), 2.83-2.08 (m, 1H), 2.02-0.98 (m, 6H).

Example 120(±)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₁H₁₉ClFN₅O₃, 427.2; m/z found 428.2 [M+H]⁺. ¹H NMR (MeOD): 8.13-7.77(m, 4H), 7.70-7.31 (m, 3H), 6.87-6.60 (m, 1H), 4.80-4.60 (m, 1H),4.51-3.67 (m, 3H), 2.84-2.22 (m, 1H), 2.07-1.11 (m, 6H).

Example 121(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-7.84 (m,3H), 7.76-7.69 (m, 1H), 7.56-6.87 (m, 3H), 6.87-6.53 (m, 1H), 4.75-4.59(m, 1H), 4.49-3.65 (m, 3H), 2.80-2.09 (m, 4H), 2.01-1.00 (m, 6H).

Example 122 (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo2.2.1 heptan-7-yl)(4-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with4-methyl-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₄H₂₃FN₄O₂, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (MeOD): 8.94-8.89 (m,1H), 8.84-8.81 (m, 1H), 8.08-7.94 (m, 2H), 7.60-7.46 (m, 1H), 7.45-7.33(m, 2H), 7.22-6.99 (m, 1H), 6.90-6.58 (m, 1H), 4.78-4.62 (m, 1H),4.52-3.78 (m, 3H), 2.73-2.19 (m, 4H), 2.07-1.05 (m, 6H).

Example 123(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-methyl-6-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with2-methyl-6-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₄H₂₃FN₄O₂, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (MeOD): 8.99-8.63 (m,2H), 8.14-7.70 (m, 2H), 7.61-7.27 (m, 4H), 7.15-6.45 (m, 1H), 4.86-4.65(m, 1H), 4.55-3.44 (m, 3H), 2.53-2.35 (m, 3H), 2.34-0.78 (m, 7H).

Example 124(±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₃H₂₀F₂N₄O₂, 422.2; m/z found 422.8 [M+H]⁺. ¹H NMR (MeOD): 9.03-8.62(m, 2H), 8.19-7.82 (m, 1H), 7.67-7.11 (m, 5H), 6.85-6.62 (m, 1H), 4.54(s, 1H), 4.26-3.76 (m, 3H), 2.33 (s, 1H), 2.01-1.32 (m, 6H).

Example 125(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.05-7.95 (m,1H), 7.93-7.84 (m, 2H), 7.57-7.05 (m, 4H), 6.81-6.65 (m, 1H), 4.61-3.98(m, 2H), 3.97-3.75 (m, 2H), 2.38-2.23 (m, 1H), 2.19-2.14 (m, 3H),1.97-1.32 (m, 6H).

Example 126(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-(hydroxymethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Step A:(±)-(5-bromo-2-(2H-1,2,3-triazol-2-yl)phenyl)(-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to example 105 substituting5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with5-bromo-2-(2H-1,2,3-triazol-2-yl)benzoic acid.

Step B: (±)-methyl3-(-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4-(2H-1,2,3-triazol-2-yl)benzoate.The title compound of step A (100 mg, 0.2 mmol) and Pd(dppf)Cl₂ (35 mg)in MeOH (10 mL) was heated to 120° C. for 24 h in a sealed tube. Thereaction was allowed to cool to rt and filtered. The filtrate wasconcentrated and purified via preparative TLC to give the title compound(20 mg, 21%).

Step C:(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-(hydroxymethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.To the title compound of step B (40 mg, 0.1 mmol)) in MeOH (0.2 mL) andTHF (6 mL) at 0° C. was added NaBH₄ (4 mg, 0.1 mmol). After stirringovernight at rt, the reaction was concentrated and purified directly viasilica gel chromatography (EtOAc in petroleum ethers) to give the titlecompound. MS (ESI) mass calcd. for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2[M+H]⁺. ¹H NMR (MeOD): 8.07-7.82 (m, 4H), 7.66-7.29 (m, 3H), 6.85-6.60(m, 1H), 4.70 (d, J=8.7 Hz, 2H), 4.50-3.73 (m, 4H), 2.43-2.20 (m, 1H),2.04-1.28 (m, 6H).

Example 127(±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₂N₄O₃, 390.2; m/z found 391.1 [M+H]⁺. ¹H NMR (MeOD): 8.12-8.00 (m,2H), 7.75-7.58 (m, 2H), 7.55-7.49 (m, 1H), 7.38-7.28 (m, 1H), 6.95-6.91(m, 1H), 6.85-6.55 (m, 1H), 4.81-4.78 (m, 1H), 4.27-4.14 (m, 1H),4.01-3.97 (m, 1H), 3.77-3.75 (m, 1H), 2.44-2.26 (m, 4H), 2.10-1.95 (m,1H), 1.87-1.62 (m, 3H), 1.56-1.46 (m, 2H).

Example 128(±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 127 substituting2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid. MS (ESI) mass calcd.for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (MeOD): 8.15-8.09(m, 1H), 7.99 (s, 2H), 7.91-7.71 (m, 1H), 7.69-6.92 (m, 3H), 6.83-6.59(m, 1H), 4.71-4.68 (m, 1H), 4.22-4.09 (m, 1H), 4.01-3.76 (m, 2H),2.64-2.52 (m, 3H), 2.43-2.23 (m, 1H), 2.00-1.36 (m, 6H).

Example 129(±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 127 substituting2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₁H₂₀FN₅O₂, 393.2; m/z found 394.0 [M+H]⁺. ¹H NMR (MeOD): 8.14-8.12 (m,1H), 7.95-7.93 (m, 2H), 7.69-7.46 (m, 2H), 7.40-7.31 (m, 1H), 7.22-7.12(m, 1H), 6.99-6.91 (m, 1H), 6.80-6.66 (m, 1H), 4.57-4.56 (m, 1H),4.04-3.88 (m, 3H), 2.38-2.27 (m, 1H), 1.85-1.43 (m, 6H).

Example 130(±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 127 substituting2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd.for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (MeOD): 8.62-8.61(m, 1H), 8.12-8.09 (m, 1H), 7.99-7.73 (m, 2H), 7.71-7.62 (m, 1H),7.50-6.91 (m, 2H), 6.87-6.61 (m, 1H), 4.74-4.71 (m, 1H), 4.17-3.79 (m,3H), 2.64-2.53 (m, 3H), 2.46-2.26 (m, 1H), 2.06-1.90 (m, 1H), 1.83-1.38(m, 5H).

Example 131(±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-10 (500 mg, 2.2 mmol) in THF (5 mL) at 0° C. was addedNaH (6.6 mmol). After 30 min at rt,2-chloro-4-(trifluoromethyl)pyrimidine (1.8 g, 9.9 mmol). The flask wasthen heated to 50° C. in an oil bath. After 3 h, H₂O was added and thereaction extracted with EtOAc (2×). Purification via silica gelchromatography (20% EtOAc in petroleum ethers) gave the title compound(752 mg, 92%).

Step B:(±)-2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptanehydrochloride. To the title compound of step A (752 mg, 2 mmol) in MeOH(6 mL) was added HCl.

Step C: (±)-tert-butyl2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to example 127 substituting2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with the title compoundof step B. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/z found 460.2[M+H]⁺. ¹H NMR (MeOD): 8.89-8.82 (m, 1H), 8.02-7.82 (m, 3H), 7.48-7.14(m, 2H), 4.75-4.71 (m, 1H), 4.44-4.07 (m, 2H), 3.91-3.84 (m, 1H),2.64-2.56 (m, 3H), 2.48-2.30 (m, 1H), 2.02-1.43 (m, 6H).

Example 132(±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd.for C₂₁H₂₀F₃N₇O₂, 459.2; m/z found 460.2 [M+H]⁺. ¹H NMR (MeOD):8.86-8.83 (m, 1H), 8.63-8.61 (m, 1H), 8.03-7.84 (m, 2H), 7.49-7.15 (m,2H), 4.76-4.72 (m, 1H), 4.41-4.31 (m, 1H), 4.27-4.04 (m, 1H), 3.90-3.84(m, 1H), 2.63-2.54 (m, 3H), 2.47-2.30 (m, 1H), 2.03-1.43 (m, 6H).

Example 133(±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₀F₃N₅O₂, 459.2; m/z found 460.2 [M+H]⁺. ¹H NMR (MeOD): 8.88-8.80(m, 1H), 8.08-8.00 (m, 1H), 7.74-7.62 (m, 1H), 7.63-7.51 (m, 1H),7.48-7.37 (m, 2H), 4.83-4.80 (m, 1H), 4.49-4.33 (m, 1H), 4.23-4.11 (m,1H), 3.81-3.77 (m, 1H), 2.53-2.36 (m, 4H), 2.07-2.98 (m, 1H), 1.90-1.51(m, 5H).

Example 134(±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₁H₁₈F₄N₆O₂, 462.2; m/z found 463.2 [M+H]⁺. ¹H NMR (MeOD): 8.89-8.84(m, 1H), 7.96-7.94 (m, 2H), 7.69-7.28 (m, 4H), 4.61-4.58 (m, 1H),4.29-4.06 (m, 2H), 3.97-3.93 (m, 1H), 2.46-2.37 (m, 1H), 1.88-1.40 (m,6H).

Example 135(±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-5-methylpyridine.MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹HNMR (MeOD): 7.99-7.71 (m, 4H), 7.51-7.00 (m, 2H), 6.73-6.50 (m, 1H),4.69 (d, J=3.6 Hz, 1H), 4.17-4.04 (m, 1H), 3.96-3.72 (m, 2H), 2.64-2.53(m, 3H), 2.43-2.20 (m, 4H), 2.03-1.35 (m, 6H).

Example 136(±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 135 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd.for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 8.62-8.55(m, 1H), 8.19-7.88 (m, 3H), 7.75-7.47 (m, 2H), 7.05-6.52 (m, 1H),4.72-4.71 (m, 1H), 4.08-4.02 (m, 1H), 3.98-3.74 (m, 2H), 2.64-2.53 (m,3H), 2.37-2.24 (m, 4H), 1.96 (brs, 1H), 1.82-1.35 (m, 5H).

Example 137(±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 135 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. forC₂₃H₂₄N₄O₃, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 8.09-8.00 (m,1H), 7.92-7.88 (m, 1H), 7.75-7.63 (m, 1H), 7.55-7.43 (m, 2H), 7.38-7.29(m, 1H), 6.76-6.47 (m, 1H), 4.81-4.77 (m, 1H), 4.22-4.09 (m, 1H), 3.95(d, J=8.1 Hz, 1H), 3.76-3.74 (m, 1H), 2.44-2.20 (m, 7H), 2.07-1.97 (m,1H), 1.86-1.62 (m, 3H), 1.55-1.42 (m, 2H).

Example 138(±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 135 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 7.96-7.93 (m,3H), 7.69-7.49 (m, 2H), 7.40-7.33 (m, 1H), 7.22-7.13 (m, 1H), 6.71-6.58(m, 1H), 4.58-4.55 (m, 1H), 4.02-3.83 (m, 3H), 2.37-2.23 (m, 4H),1.85-1.41 (m, 6H).

Example 139(±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 135 substituting2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-6-methylpyridine.MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹HNMR (MeOD): 7.99 (s, 2H), 7.91-7.69 (m, 1H), 7.56-6.77 (m, 3H),6.60-6.38 (m, 1H), 4.70-4.69 (m, 1H), 4.21-4.05 (m, 1H), 3.98-3.77 (m,2H), 2.64-2.51 (m, 3H), 2.43-2.20 (m, 4H), 2.03-1.37 (m, 6H).

Example 140(±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 139 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd.for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 8.34 (d,J=7.1 Hz, 1H), 7.77-7.42 (m, 3H), 7.28-6.35 (m, 3H), 4.82-4.79 (m, 1H),4.24-3.94 (m, 2H), 3.87-3.81 (m, 1H), 2.63-2.22 (m, 7H), 2.15-1.98 (m,1H), 1.84-1.34 (m, 5H).

Example 141(±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 139 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. forC₂₃H₂₄N₄O₃, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-8.00 (m,1H), 7.75-7.63 (m, 1H), 7.57-7.47 (m, 2H), 7.37-7.26 (m, 1H), 6.79 (dd,J=7.2, 2.8 Hz, 1H), 6.64-6.35 (m, 1H), 4.81-4.78 (m, 1H), 4.25-4.11 (m,1H), 3.98-3.95 (m, 1H), 3.79-3.74 (m, 1H), 2.42-2.25 (m, 7H), 2.08-1.95(m, 1H), 1.86-1.63 (m, 3H), 1.58-1.44 (m, 2H).

Example 142(±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 139 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 7.95-7.93 (m,2H), 7.68-7.47 (m, 2H), 7.40-7.31 (m, 1H), 7.21-7.09 (m, 1H), 6.80 (t,J=8.3 Hz, 1H), 6.58-6.46 (m, 1H), 4.56 (s, 1H), 4.01 (d, J=7.3 Hz, 1H),3.91 (d, J=7.4 Hz, 2H), 2.43 (d, J=2.5 Hz, 3H), 2.38-2.28 (m, 1H),1.83-1.45 (m, 6H).

Example 143(±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting2-chloro-4-(trifluoromethyl)pyrimidine with2-chloro-6-(trifluoromethyl)pyridine. MS (ESI) mass calcd. forC₂₂H₂₁F₃N₆O₂, 458.2; m/z found 459.2 [M+H]⁺. ¹H NMR (MeOD): 7.91 (s,1H), 7.84 (s, 1H), 7.73-7.65 (m, 2H), 7.29-7.25 (m, 2H), 6.93-6.69 (m,1H), 4.85-4.82 (m, 1H), 4.25-4.16 (m, 1H), 3.98-3.96 (m, 1H), 3.79-3.69(m, 1H), 2.69-2.56 (m, 3H), 2.38-2.16 (m, 1H), 2.05-1.24 (m, 6H).

Example 144(±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 143 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd.for C₂₂H₂₁F₃N₆O₂, 458.2; m/z found 459.2 [M+H]⁺. ¹H NMR (MeOD): 8.61 (t,J=1.1 Hz, 1H), 8.00-7.72 (m, 3H), 7.49-6.83 (m, 3H), 4.75-4.71 (m, 1H),4.31-4.10 (m, 1H), 4.08-3.95 (m, 1H), 3.89-3.77 (m, 1H), 2.64-2.52 (m,3H), 2.43-2.27 (m, 1H), 2.06-1.89 (m, 1H), 1.82-1.37 (m, 5H).

Example 145(±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 143 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. forC₂₃H₂₁FN₄O₃, 458.2; m/z found 459.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-8.01 (m,1H), 7.88-7.77 (m, 1H), 7.75-7.63 (m, 1H), 7.54-7.49 (m, 1H), 7.39-7.25(m, 2H), 7.07-6.78 (m, 1H), 4.82-4.79 (m, 1H), 4.35-4.24 (m, 1H),4.10-4.07 (m, 1H), 3.78-3.74 (m, 1H), 2.48-2.29 (m, 4H), 2.09-1.96 (m,1H), 1.88-1.63 (m, 3H), 1.58-1.47 (m, 2H).

Example 146(±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 143 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₁₉F₄N₅O₂, 461.2; m/z found 462.0 [M+H]⁺. ¹H NMR (MeOD): 7.95-7.93(m, 2H), 7.86-7.80 (m, 1H), 7.68-7.12 (m, 4H), 7.02-6.86 (m, 1H),4.59-4.56 (m, 1H), 4.10-3.86 (m, 3H), 2.38-2.30 (m, 1H), 1.95-1.45 (m,6H).

Example 147(±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloroquinoxaline. MS(ESI) mass calcd. for C₂₄H₂₃N₇O₂, 441.2; m/z found 442.2 [M+H]⁺. ¹H NMR(MeOD): 8.47-8.04 (m, 2H), 7.98-7.69 (m, 5H), 7.65-7.56 (m, 1H),7.45-6.73 (m, 1H), 4.77-4.71 (m, 1H), 4.46-4.10 (m, 2H), 3.91-3.79 (m,1H), 2.64-2.32 (m, 4H), 2.03-1.38 (m, 6H).

Example 148(±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 147 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd.for C₂₄H₂₃N₇O₂, 441.2; m/z found 441.2 [M+H]⁺. ¹H NMR (MeOD): 8.61-8.59(m, 1H), 8.46-8.25 (m, 1H), 8.04-7.55 (m, 6H), 7.48-6.74 (m, 1H),4.78-4.74 (m, 1H), 4.43-4.30 (m, 1H), 4.21-4.18 (m, 1H), 3.92-3.82 (m,1H), 2.63-2.34 (m, 4H), 2.08-1.89 (m, 1H), 1.88-1.39 (m, 5H).

Example 149(±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 147 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. forC₂₅H₂₃N₅O₃, 441.2; m/z found 442.2 [M+H]⁺. ¹H NMR (MeOD): 8.48-8.20 (m,1H), 8.08-7.91 (m, 2H), 7.83-7.12 (m, 6H), 4.86-4.81 (m, 1H), 4.50-4.36(m, 1H), 4.26-4.18 (m, 1H), 3.80-3.77 (m, 1H), 2.55-2.34 (m, 4H),2.09-1.97 (m, 1H), 1.91-1.64 (m, 3H), 1.61-1.50 (m, 2H).

Example 150(±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 147 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₄H₂₁FN₆O₂, 444.2; m/z found 445.1 [M+H]⁺. ¹H NMR (MeOD): 8.47-8.33 (m,1H), 8.01-7.60 (m, 6H), 7.54-6.92 (m, 3H), 4.65-4.60 (m, 1H), 4.31-4.13(m, 2H), 3.96-3.95 (m, 1H), 2.52-2.40 (m, 1H), 1.96-1.44 (m, 6H).

Example 151(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone

Prepared analogous to Example 131 substituting2-chloro-4-(trifluoromethyl)pyrimidine with2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C₂₂H₂₅N₇O₂,419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (MeOD): 8.02-7.99 (m, 2H),7.94-7.46 (m, 1H), 7.48-7.10 (m, 1H), 6.87 (s, 1H), 4.72-4.71 (m, 1H),4.38-3.97 (m, 2H), 3.89-3.84 (m, 1H), 2.65-2.17 (m, 10H), 1.98-1.37 (m,6H).

Example 152(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methanone

Prepared analogous to Example 151 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd.for C₂₂H₂₅N₇O₂, 419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (MeOD): 8.62-8.61(m, 1H), 7.98-7.78 (m, 2H), 7.50-7.11 (m, 1H), 6.86 (d, J=9.7 Hz, 1H),4.75-4.71 (m, 1H), 4.25-4.23 (m, 1H), 4.16-3.84 (m, 2H), 2.64-2.55 (m,3H), 2.46-2.25 (m, 7H), 2.06-1.88 (m, 1H), 1.85-1.39 (m, 5H).

Example 153(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)methanone

Prepared analogous to Example 151 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. forC₂₃H₂₅N₅O₃, 419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-8.01 (m,1H), 7.76-7.64 (m, 1H), 7.58-7.51 (m, 1H), 7.42-7.36 (m, 1H), 6.86 (s,1H), 4.83-4.80 (m, 1H), 4.42-4.22 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.76(m, 1H), 2.49-2.28 (m, 10H), 2.08-1.98 (m, 1H), 1.89-1.65 (m, 3H),1.58-1.48 (m, 2H).

Example 154(±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 151 substituting6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. forC₂₂H₂₃FN₆O₂, 422.2; m/z found 423.1 [M+H]⁺. ¹H NMR (MeOD): 7.96-7.95 (m,2H), 7.69-7.22 (m, 3H), 6.87 (d, J=5.8 Hz, 1H), 4.58-4.56 (m, 1H),4.19-3.89 (m, 3H), 2.42-2.34 (m, 7H), 1.90-1.37 (m, 6H).

Example 155(±)-(2-ethoxy-4-methylpyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with B-10and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with2-ethoxy-4-methylnicotinic acid. MS (ESI) mass calcd. for C₂₁H₂₅N₃O₃,367.2; m/z found 368.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.13-8.05 (m, 1H),7.99-7.87 (m, 1H), 7.58-7.46 (m, 1H), 6.87-6.79 (m, 1H), 6.76-6.67 (m,1H), 6.55-6.49 (m, 1H), 4.92-4.84 (m, 1H), 4.43-3.64 (m, 5H), 2.43-1.22(m, 13H).

Example 156(±)-(6-methylimidazo[2,1-b]thiazol-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with B-10and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with6-methylimidazo[2,1-b]thiazole-5-carboxylic acid. ¹H NMR (CDCl₃):8.05-7.98 (m, 1H), 7.79 (d, J=4.5 Hz, 1H), 7.54-7.47 (m, 1H), 6.84-6.78(m, 1H), 6.76 (d, J=4.5 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.54-4.35 (m,2H), 4.11-4.03 (m, 1H), 4.02-3.88 (m, 1H), 2.46 (s, 3H), 2.39-2.28 (m,1H), 2.07-1.97 (m, 1H), 1.80-1.70 (m, 2H), 1.65-1.52 (m, 3H).

Example 157(±)-(5-bromo-2-ethoxypyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with B-10and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with5-bromo-2-ethoxynicotinic acid. MS (ESI) mass calcd. for C₂₀H₂₂BrN₃O₃,431.1; m/z found 432.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.33-8.07 (m, 2H), 7.74(d, J=2.5 Hz, 0.5H), 7.61 (d, J=2.5 Hz, 0.5H), 7.59-7.49 (m, 1H),6.89-6.81 (m, 1H), 6.75 (d, J=8.3 Hz, 0.5H), 6.55 (d, J=8.4 Hz, 0.5H),4.86-4.80 (m, 1H), 4.48-3.78 (m, 5H), 2.43-2.33 (m, 0.5H), 2.32-2.23 (m,0.5H), 2.03-1.39 (m, 6H), 1.37-1.29 (m, 3H).

Example 158(±)-(2-ethoxy-6-methylpyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with2-ethoxy-6-methylnicotinic acid. MS (ESI) mass calcd. for C₂₁H₂₅N₃O₃,367.2; m/z found 368.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.14-8.08 (m, 1H),7.57-7.47 (m, 1.5H), 7.38 (d, J=7.4 Hz, 0.5H), 6.86-6.82 (m, 1H), 6.74(d, J=8.3 Hz, 0.5H), 6.72 (d, J=7.4 Hz, 0.5H), 6.51 (d, J=8.3 Hz, 0.5H),6.46 (d, J=7.4 Hz, 0.5H), 4.84-4.79 (m, 1H), 4.44-4.34 (m, 1.5H),4.27-4.09 (m, 1.5H), 4.06-4.01 (m, 0.5H), 3.92-3.80 (m, 1.5H), 2.43 (s,1.5H), 2.38-2.32 (m, 2H), 2.26-2.20 (m, 0.5H), 2.01-1.40 (m, 6H),1.36-1.28 (m, 3H).

Example 159(±)-(7-hydroxyquinolin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with7-hydroxyquinoline-8-carboxylic acid (intermediate A-29 step B). MS(ESI) mass calcd. for C₂₂H₂₁N₃O₃, 375.2; m/z found 376.3 [M+H]⁺. ¹H NMR(CDCl₃): 8.88-8.66 (m, 1H), 8.19-7.93 (m, 2H), 7.80-7.41 (m, 2H),7.26-6.25 (series of m, 4H), 5.10-4.87 (m, 1H), 4.34-3.60 (m, 3H),2.51-1.00 (series of m, 7H).

Example 160(±)-(2-ethoxy-5-phenylpyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-1)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with2-ethoxy-5-phenylnicotinic acid. MS (ESI) mass calcd. for C₂₆H₂₇N₃O₃,429.2; m/z found 430.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.40 and 8.30 (2d, J=2.5Hz, 1H), 8.15-8.12 and 7.98-7.94 (2m, 1H), 7.87 and 7.74 (2d, J=2.5 Hz,1H), 7.59-7.28 (m, 6H), 6.88-6.83 and 6.72-6.68 (2m, 1H), 6.76 and 6.47(2d, J=8.3 Hz, 1H), 4.89-4.84 (m, 1H), 4.34-3.84 (series of m, 5H),2.43-2.34 and 2.32-2.23 (m, 1H), 2.06-1.45 (series of m, 6H), 1.42-1.32(m, 3H).

Example 161(±)-(4-bromo-2-ethoxypyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with4-bromo-2-ethoxynicotinic acid. MS (ESI) mass calcd. for C₂₀H₂₂BrN₃O₃,431.1; m/z found 432.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.15-8.08 (m, 1H),7.96-7.87 (m, 1H), 7.60-7.49 (m, 1H), 7.11-6.92 (series of m, 1H),6.88-6.82 (m, 1H), 6.78-6.52 (series of m, 1H), 4.94-4.87 (m, 1H),4.47-3.67 (series of m, 5H), 2.45-1.41 (series of m, 7H), 1.38-1.27 (m,3H).

Example 162(±)-(2-chloro-4-ethoxypyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with2-chloro-4-ethoxynicotinic acid. MS (ESI) mass calcd. for C₂₀H₂₂ClN₃O₃,387.1; m/z found 388.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.27-8.17 (m, 1H),8.15-8.07 (m, 1H), 7.60-7.48 (m, 1H), 6.88-6.82 (m, 1H), 6.80-6.73 (m,1H), 6.58-6.49 (m, 1H), 4.93-4.87 (m, 1H), 4.27-4.02 (m, 3H), 3.92-3.58(series of m, 2H), 2.44-1.35 (series of m, 10OH).

Example 163(±)-(2,4-diethoxypyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with2,4-diethoxynicotinic acid. MS (ESI) mass calcd. for C₂₂H₂₇BrN₃O₄,397.2; m/z found 398.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.15-8.07 (m, 1H),8.03-7.94 (m, 1H), 7.60-7.46 (m, 1H), 6.87-6.80 (m, 1H), 6.77-6.73 (m,0.5H), 6.56-6.45 (m, 1H), 6.30-6.27 (m, 0.5 H) 4.88-4.83 (m, 1H),4.50-3.51 (series of m, 7H), 2.40-1.15 (series of m, 13H).

Example 164(3-ethoxyisoquinolin-4-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting5-fluoro-2-(pyrimidin-2-yl)benzoic acid with intermediate A-22. MS (ESI)mass calcd. for C₂₄H₂₅N₃O₃, 403.2; m/z found 404.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) 8.97-8.89 (m, 0.7H), 8.87-8.81 (m, 0.3H), 8.22-8.07 (m,0.7H), 7.95-7.85 (m, 1H), 7.82 (dq, J=8.6, 0.9 Hz, 0.2H), 7.78-7.69 (m,0.6H), 7.69-7.47 (m, 2H), 7.43-7.28 (m, 1.2H), 7.10 (ddd, J=8.0, 6.8,1.0 Hz, 0.3H), 6.93-6.68 (m, 1.5H), 6.52-6.46 (m, 0.2H), 6.16-6.09 (m,0.3H), 5.02 (td, J=9.5, 4.6 Hz, 1H), 4.65-3.99 (m, 3.5H), 3.92 (dd,J=10.5, 5.6 Hz, 0.25H), 3.74-3.58 (m, 1.25H), 2.52-2.29 (m, 0.5H),2.27-1.93 (m, 2H), 1.86-0.78 (m, 7.5H).

Example 165(±)-(2-ethoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 7 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with 2-ethoxybenzoicacid. ¹H NMR (400 MHz, CDCl₃): 7.95 (dd, J=7.3, 3.1 Hz, 1H), 7.37-7.18(m, 2.5H), 7.14 (dd, J=7.4, 1.7 Hz, 0.5H), 6.95 (td, J=7.5, 0.9 Hz,0.5H), 6.90 (dd, J=8.4, 1.0 Hz, 0.5H), 6.83-6.68 (m, 1.5H), 6.47 (dd,J=9.0, 3.6 Hz, 0.5H), 4.88-4.80 (m, 1H), 4.17-3.72 (m, 5H), 2.40-2.28(m, 0.5H), 2.26-2.14 (m, 0.5H), 2.07-1.85 (m, 2H), 1.83-1.17 (m, 7H).

Example 166(±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with intermediate A-10and 2-fluoropyridine with 2-chloroquinoxaline. MS (ESI) mass calcd. forC₂₄H₂₁FN₆O₂, 444.2; m/z found 445.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.49 (s, 0.4H), 8.30 (s, 0.4H), 8.04 (ddd, J=8.2, 6.9, 1.5 Hz, 1H),7.90-7.76 (m, 2.5H), 7.75-7.66 (m, 1.5H), 7.65-7.55 (m, 1.5H), 7.44 (dd,J=8.5, 5.8 Hz, 0.5H), 7.32 (dd, J=8.5, 5.8 Hz, 0.5H), 7.29-7.22 (m,0.2H), 7.21-7.10 (m, 1H), 6.49 (s, 0.5H), 4.93-4.84 (m, 1H), 4.52-4.30(m, 1H), 4.23-4.07 (m, 1H), 3.87-3.78 (m, 1H), 2.48-2.25 (m, 1.8H),2.10-1.88 (m, 1.2H), 1.83-1.31 (m, 4H).

Example 167(±)-5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-trfluoromethylpyrimidine with 2-fluoro-5-methylpyridine. MS(ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.99-7.92 (m, 1H), 7.81-7.68 (m, 2.5H), 7.42-7.29 (m,1.5H), 7.26-7.21 (m, 0.5H), 7.21-7.10 (m, 1H), 6.66 (d, J=8.4 Hz, 0.5H),6.45 (d, J=8.4 Hz, 0.5H), 4.85-4.73 (m, 1H), 4.16-3.68 (m, 3H), 2.42 (s,1.3H), 2.34-2.14 (m, 3.7H), 2.02-1.79 (m, 2.5H), 1.72-1.21 (m, 5.5H).

Example 168(±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 withintermediate B-10, 2-fluoropyridine with 2-chloroquinoxaline and5-fluoro-2-(pyrimidin-2-yl)benzoic acid with intermediate A-3 to givethe title compound. MS (ESI) mass calcd. for C₂₄H₂₃N₇O₂, 441.2; m/zfound 442.2 [M+H]⁺. ¹H NMR CD₃OD: 8.47-8.04 (m, 2H), 7.98-7.69 (m, 5H),7.65-7.56 (m, 1H), 7.45-6.73 (m, 1H), 4.77-4.71 (m, 1H), 4.46-4.10 (m,2H), 3.91-3.79 (m, 1H), 2.64-2.32 (m, 4H), 2.03-1.38 (m, 6H).

Example 169(±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((pyridin-2-ylamino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 170 substituting2-chloro-4,6-dimethylpyrimidine with 2-fluoropyridine. MS (ESI) masscalcd. for C₂₁H₂₁FN₆O, 392.2; m/z found 393.1 [M+H]⁺. 1H NMR (CD3OD):8.02-7.83 (m, 4H), 7.47-7.23 (m, 3H), 6.59-6.38 (m, 2H), 4.73-4.55 (m,1H), 3.87-3.70 (m, 1H), 3.24-2.80 (m, 2H), 2.27-2.03 (m, 1H), 1.97-1.34(m, 6H).

Example 170(±)-(2-(((4,6-dimethylpyrimidin-2-yl)amino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Step A: (±)-tert-butyl2-(((methylsulfonyl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-10 (2.6 g, 11.5 mmol) and TEA (1.7 g, 17.2 mmol) inDCM (15 mL) at 0° C. was added MsCl (1.6 g, 13.7 mmol) dropwise over10m. This ice bath was removed and the reaction was allowed to proceedat rt for 12 h and H2O was added. The layers were separated and theorganic layer was washed with brine and dried (Na2SO4). Purification viasilica gel chromatography (15% EtOAc in petroleum ethers) gave the titlecompound (3.5 g).

Step B: (±)-tert-butyl2-(azidomethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To the titlecompound of step A (3.4 g, 11.1 mmol) in DMF (15 mL) was added sodiumazide (2.1 g, 33.4 mmol). The mixture was heated at 100° C. overnight,cooled to rt, poured into H₂O and extracted with DCM. The combinedorganics were washed with brine and dried (Na₂SO₄). Purification viasilica gel chromatography (10% EtOAc in petroleum ethers) gave the titlecompound (2.6 g).

Step C: (±)-2-(azidomethyl)-7-azabicyclo[2.2.1]heptane. To the titlecompound of step B in DCM was added TFA. After 3 h at rt, the reactionmixture was concentrated to give the title compound (1.7 g) as the TFAsalt.

Step D:(±)-2-(azidomethyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.Prepared analogous to example 22 substituting2-(2H-1,2,3-triazol-2-yl)benzoic acid with5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid and using the titlecompound of step C.

Step E:2-(aminomethyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.The title compound of step D in MeOH was hydrogenated under anatmosphere of hydrogen in the presence of 10 wt % Pd/C for 4 h. Thecatalyst was removed by filtration. Purification via silica gelchromatography (7% MeOH in DCM) gave the title compound.

Step F:(±)-(2-(((4,6-dimethylpyrimidin-2-yl)amino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.To the title compound of step E (30 mg) in NMP (3 mL) was added2-chloro-4,6-dimethylpyrimidine (16 mg) and Cs₂CO₃ (43 mg). The reactionwas heated to 180° C. for 2 h. After cooling to rt, H₂O was added andthe mixture extracted with EtOAc. Purification via prep-HPLC gave thetitle compound. MS (ESI) mass calcd. for C22H₂₄FN₇O, 421.2; m/z found422.2 [M+H]⁺. ¹H NMR (CD3OD) 7.90-7.73 (m, 3H), 7.34-7.14 (m, 2H),6.31-6.26 (m, 1H), 4.62-4.41 (m, 1H), 3.74-3.57 (m, 1H), 3.46-3.22 (m,1H), 3.18-2.93 (m, 1H), 2.40-1.91 (m, 7H), 1.85-1.20 (m, 6H).

Example 171(±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 170 substituting2-chloro-4,6-dimethylpyrimidine with2-chloro-4-(trifluoromethyl)pyrimidine. MS (ESI) mass calcd. forC₂₁H₁₉F₄N₇O, 461.2; m/z found 462.1 [M+H]⁺. 1H NMR (CD3OD): 8.51 (s,1H), 7.99-7.83 (m, 3H), 7.46-7.16 (m, 2H), 6.88 (d, J=4.9 Hz, 1H),4.74-4.53 (m, 1H), 3.87-3.66 (m, 1H), 3.34 (s, 1H), 3.30-3.02 (m, 1H),2.33-2.08 (m, 1H), 1.97-1.32 (m, 6H).

Example 172(±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 170 substituting2-chloro-4,6-dimethylpyrimidine with2-chloro-6-(trifluoromethyl)pyridine. MS (ESI) mass calcd. forC₂₂H₂₀F₄N₆O, 460.2; m/z found 461.2 [M+H]⁺. 1H NMR (CD3OD): 8.07-7.84(m, 3H), 7.60-7.22 (m, 3H), 6.90 (d, J=7.2 Hz, 1H), 6.74-6.58 (m, 1H),4.77-4.58 (m, 1H), 3.90-3.72 (m, 1H), 3.30-3.05 (m, 2H), 2.37-2.12 (m,1H), 1.99-1.37 (m, 6H).

Example 173(±)-(3-fluoro-2-methoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 7 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₂₀F₂N₂O₃,374.1; m/z found 375.1 [M+H]⁺. 1H NMR (CD3OD): 8.01-7.90 (m, 1H),7.56-7.38 (m, 1H), 7.28-7.06 (m, 2H), 7.02-6.53 (m, 2H), 4.82-4.66 (m,1H), 4.50-3.73 (m, 6H), 2.85-2.22 (m, 1H), 2.21-1.10 (m, 6H).

Example 174(±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-ylamino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 170 substituting2-chloro-4,6-dimethylpyrimidine with 2-chloroquinoxaline. MS (ESI) masscalcd. for C₂₄H₂₂FN₇O, 443.2; m/z found 444.2 [M+H]⁺.

Example 175(±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with intermediateA-9. MS (ESI) mass calcd. for C₂₂H₂₁FN₆O₂, 420.2; m/z found 421 [M+H]⁺.

Example 176(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((3-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 7 substituting 5-fluoropyridin-2(1H)-onewith 3-methylpyridin-2-ol. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2;m/z found 405 [M+H.

Example 177(±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(4-methyloxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with intermediate A-54.MS (ESI) mass calcd. for C₂₃H₂₃FN₄O₃, 422.2; m/z found 423 [M+H]⁺.

Example 178(6-methyl-3-(4-methyloxazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate A-7 withintermediate A-54. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₃, 404.2; m/z found405 [M+H]⁺.

Example 179((1S,2R,4R)-2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(4-methyloxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 98 substituting intermediate3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with intermediateA-54. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424 [M+H]⁺.

Example 180(±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting2-chloro-4-(trifluoromethyl)pyrimidine with4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine. MS (ESI) mass calcd.for C₂₃H₂₃F₃N₆O₂, 472.2; m/z found 473.2 [M+H]⁺. ¹H NMR (CDCl₃):7.88-7.72 (m, 3H), 7.38-7.12 (m, 2H), 6.74-6.70 (s, 0.6H), 6.55-6.50 (s,0.4H), 4.89-4.75 (m, 1H), 4.30-3.87 (m, 2H), 3.85-3.46 (m, 1H),2.56-2.49 (m, 3H), 2.46-2.39 (s, 2H), 2.32-1.80 (m, 3H), 1.74-1.11 (m,5H).

Example 181(2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-5 (1.6 g, 7.3 mmol) and K₂CO₃ (1.5 g, 10 mmol) in DMF(11 mL) was added 2-chloro-5-(trifluoromethyl)pyrazine (1.1 mL, 8.8mmol). After heating at 70° C. for 2 h, the mixture was cooled to rt,diluted with EtOAc and H₂O. The aqueous layer was extracted with EtOAc(3×). The combined organics were washed with 4% (aq) and dried (MgSO₄).Purification via silica gel chromatography (0-40% EtOAc in hexanes) gavethe title compound (1.8 g, 67%). MS (ESI) mass calcd. for C₁₆H₂₁F₃N₄O₂,358.2; m/z found 359.2 [M+H]⁺. ¹H NMR (CDCl3): 8.32 (s, 1H), 7.86-7.82(m, 1H), 5.33 (s, 1H), 4.38-4.15 (m, 2H), 4.10-3.96 (m, 1H), 2.14-1.98(m, 1H), 1.93-1.67 (m, 2H), 1.61-1.36 (m, 12H).

Step B:(1S,2R,4R)—N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine.To the title compound of step A (200 mg, 0.6 mmol) in EtOAc (1 mL) wasadded 4M HCl in dioxane (3 mL). After 2 h, the reaction wasconcentrated, neutralized with 5% Na₂CO₃ (aq) and extracted with DCM(2×). The combined organics were dried (Na₂SO₄) to give the titlecompound of step B that was used without further purification. MS (ESI)mass calcd. for C₁₁H₁₃F₃N₄, 258.1; m/z found 259.1 [M+H]⁺.

Step C:(2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.To the title compound of step B (140 mg, 0.5 mmol) and intermediate A-1(113 mg, 0.6 mmol) in DMF (4 mL) was added DIPEA (230 μL, 1.4 mmol) andHATU (155 mg, 0.6 mmol). Upon completion of the reaction, purificationwas performed using Agilent prep method X to give the title compound(172 mg, 74%). MS (ESI) mass calcd. for C₂₀H₁₈F₃N₇O, 429.2; m/z found430 [M+H]⁺. ¹H NMR (CDCl3): 8.32 (s, 0.3H), 8.17 (s, 0.7H), 7.99-7.89(m, 1.5H), 7.88-7.77 (m, 1.5H), 7.62-7.30 (m, 4H), 6.24-6.15 (m, 0.3H),4.86 (s, 0.7H), 4.76 (d, J=5.4 Hz, 0.3H), 4.45-4.23 (m, 1H), 4.08-3.90(m, 1H), 2.23-1.34 (m, 6H).

Example 182(±)-((2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to Example 181 step A substituting intermediate B-5with intermediate B-6.

Step B:(±)-N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine.Prepared analogous to Example 181 step B substituting(1S,2R,4R)-tert-butyl2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylatewith (±)-tert-butyl2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.

Step C:(±)-((2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.

To 2-(2H-1,2,3-triazol-2-yl)benzoic acid (125 mg, 0.6 mmol) and DMF (4mL) was added (i-Pr)₂NEt (0.23 mL, 1.3 mmol) and HBTU (155 mg, 0.6mmol). After 10 min, the title compound from step B (146 mg. 0.4 mmol)was added. After stirring overnight at rt, saturated NaHCO₃ (aq.) wasadded and the mixture extracted with EtOAc (3×). The combined organicswere dried (MgSO₄) and concentrated. Purification via preparative HPLCgave the title compound (89 mg, 47%) as a beige solid. MS (ESI) masscalcd. for C₂₀H₁₈F₃N₇O, 429.2; m/z found 430 [M+H]⁺. ¹H NMR (DMSO-D₆):8.47 (s, 0.3H), 8.24 (s, 0.7H), 8.14-8.05 (m, 2.2H), 8.02 (s, 0.7H),7.85 (d, J=7.2 Hz, 1.3H), 7.72-7.55 (m, 1.7H), 7.49-7.34 (m, 1.4H), 7.13(t, J=7.4 Hz, 0.7H), 4.58 (t, J=4.3 Hz, 0.7H), 4.44 (d, J=4.7 Hz, 0.3H),4.04-3.93 (m, 0.3H), 3.82 (t, J=4.1 Hz, 0.3H), 3.79-3.70 (m, 0.7H), 3.54(d, J=4.8 Hz, 0.7H), 2.07-1.90 (m, 1H), 1.85-1.07 (m, 5H).

Example 183a(2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

and Example 183 b(2-(2H-1,2,3-triazol-2-yl)phenyl)((1R,2S,4S)-2-((5-trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK OD-H 5 μM250×20 mm) resolution of Example 182 (81 mg) using 70% CO₂/30% EtOH asthe mobile phase to give enantiomer A (37 mg, 1st eluting enantiomer,example 183a) and enantiomer B (38 mg, 2^(nd) eluting enantiomer,example 183b). Example 183a: >98% single enantiomer, 2.45 min retentiontime; Example 183b>98% single enantiomer, 3.33 min retention time.

Example 183a: Enantiomer A: MS (ESI) mass calcd. for C₂₀H₁₈F₃N₇O, 429.2;m/z found 430 [M+H]⁺.

Example 183b: Enantiomer B: MS (ESI) mass calcd. for C₂₀H₁₈F₃N₇O, 429.2;m/z found 430 [M+H]⁺.

Example 184(±)-(5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 182 substituting intermediate A-1 withintermediate A-19 and HBTU with HATU. MS (ESI) mass calcd. forC₂₀H₁₉F₃N₈O, 444.2; m/z found 445.1 [M+H]⁺.

Example 185(±)-(5-methyl-3-(1H-1,2,3-triazol-1-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 184 substituting intermediate A-19 withintermediate A-20. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/zfound 445.1 [M+H]⁺. HPLC R_(t)=1.13.

Example 186(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 184 substituting intermediate A-19 withintermediate A-21. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/zfound 445.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.36-8.32 (s, 0.2H), 8.27-8.23 (s,0.8H), 8.22-8.18 (d, J=8.4 Hz, 0.2H), 8.13-8.08 (d, J=8.3 Hz, 0.8H),7.93-7.84 (m, 2H), 7.79-7.75 (m, 0.8H), 7.40-7.36 (d, J=8.4 Hz, 0.2H),7.36-7.31 (d, J=8.4 Hz, 0.8H), 7.26-7.22 (m, 0.2H), 6.26-6.19 (d, J=8.5Hz, 0.2H), 4.96-4.86 (t, J=4.8 Hz, 0.8H), 4.83-4.75 (d, J=5.4 Hz, 0.2H),4.36-4.19 (m, 1H), 4.13-3.92 (d, J=5.0 Hz, 1H), 2.69-2.56 (m, 3H),2.29-2.14 (dd, J=13.1, 7.5 Hz, 1H), 2.14-1.87 (m, 2H), 1.81-1.78 (m,1H), 1.63-1.56 (m, 2H).

Example 187(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-6 (150 mg, 0.7 mmol) in DMSO (10 mL) was added DIPEA(244 μL, 1.4 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (170 μL, 1.4mmol). After heating at 100° C. for 4 h, the mixture was cooled to rtand saturated NaHCO₃ (aq) was added. The mixture was extracted with DCM(3×). The combined organics were washed with brine and dried (MgSO₄).Purification via silica gel chromatography (0-13% EtOAc in heptanes)gave the title compound. MS (ESI) mass calcd. for C₁₇H₂₂F₃N₇O₂, 357.2;m/z found 358.0 [M+H]⁺.

Step B:(±)-N-(5-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-aminehydrochloride. To the title compound from step A (262 mg, 0.7 mmol) in1,4-dioxane (10 mL) was added 6N HCl in iPrOH (700 μL). The reaction washeated to 70° C. for 2 h, cooled to rt, concentrated and used withoutfurther purification in subsequent steps.

Step C:(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.

Prepared analogous to Example 182 substituting intermediate A-1 withintermediate A-21 and(±)-N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-aminewith the title compound of step B. MP=193.9° C. ¹H NMR (DMSO-D₆): 8.38(s, 0.3H), 8.24-8.16 (m, 1H), 8.15-8.11 (m, 2H), 8.05 (d, J=8.3 Hz,0.7H), 7.69 (dd, J=8.9, 2.3 Hz, 0.3H), 7.63 (dd, J=8.9, 2.4 Hz, 0.7H),7.57 (d, J=8.4 Hz, 0.3H), 7.37 (d, J=8.4 Hz, 0.7H), 7.33 (d, J=5.8 Hz,0.7H), 7.14 (d, J=4.5 Hz, 0.3H), 6.75 (d, J=8.9 Hz, 0.3H), 6.61 (d,J=8.9 Hz, 0.7H), 4.60 (t, J=4.5 Hz, 0.7H), 4.51 (d, J=4.8 Hz, 0.3H),3.99-3.90 (m, 0.6H), 3.89-3.77 (m, 1.4H), 2.60 (s, 0.9H), 2.23 (s,2.1H), 1.99 (dd, J=12.6, 7.6 Hz, 1H), 1.83-1.21 (m, 5H).

Example 188(±)-(5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-19. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.2; m/zfound 444.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.49-8.44 (dd, J=1.9, 0.9 Hz, 0.2H),8.41-8.32 (m, 1H), 8.28-8.21 (m, 0.8H), 8.18-8.11 (m, 0.2H), 8.06-7.98(m, 0.8H), 7.94-7.86 (m, 2H), 7.60-7.53 (dd, J=8.8, 2.4 Hz, 0.2H),7.45-7.35 (dd, J=8.9, 2.4 Hz, 0.8H), 6.71-6.59 (d, J=8.7 Hz, 0.8H),6.45-6.37 (d, J=8.8 Hz, 0.2H), 6.27-6.17 (d, J=8.8 Hz, 0.8H), 5.82-5.72(m, 0.2H), 4.95-4.84 (t, J=4.6 Hz, 0.8H), 4.82-4.74 (d, J=5.2 Hz, 0.2H),4.36-4.18 (m, 1H), 4.08-3.97 (m, 1H), 2.51-2.47 (s, 0.7H), 2.45-2.41 (m,2.3H), 2.22-2.14 (dd, J=13.0, 7.7 Hz, 0.8H), 2.11-1.90 (m, 2.2H),1.82-1.40 (m, 3H).

Example 189(±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-3. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.2; m/z found444.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.33 (s, 0.4H), 8.26-8.19 (d, J=2.0Hz, 0.6H), 7.98-7.88 (m, 2H), 7.78-7.71 (d, J=7.7 Hz, 0.4H), 7.64-7.55(m, 1H), 7.41-7.27 (m, 1.6H), 7.20-7.08 (m, 0.7H), 6.43-6.35 (d, J=8.8Hz, 0.3H), 6.13-6.01 (d, J=8.7 Hz, 0.7H), 5.74-5.56 (m, 0.3H), 4.90-4.81(m, 0.7H), 4.78-4.71 (d, J=5.3 Hz, 0.3H), 4.38-4.14 (m, 1H), 3.99-3.85(m, 1H), 2.78-2.55 (m, 3H), 2.24-2.10 (dd, J=13.2, 7.9 Hz, 1H),2.08-1.39 (m, 5H).

Example 190(±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-4. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.2; m/z found444.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.50-8.46 (m, 0.6H), 8.37-8.34 (d, J=1.2Hz, 0.4H), 8.34-8.31 (s, 0.6H), 8.24-8.17 (s, 0.4H), 7.90-7.84 (m, 1H),7.75-7.69 (d, J=7.7 Hz, 0.6H), 7.65-7.60 (d, J=7.8 Hz, 0.4H), 7.55-7.47(dd, J=8.7, 2.4 Hz, 0.7H), 7.36-7.27 (m, 1.3H), 7.22-7.14 (m, 0.4H),6.94-6.83 (d, J=8.7 Hz, 0.6H), 6.29-6.11 (d, J=8.9 Hz, 1H), 4.91-4.74(d, J=5.3 Hz, 1H), 4.55-4.28 (m, 1H), 4.04-3.90 (m, 1H), 2.66-2.62 (s,1.9H), 2.59-2.55 (s, 1.1H), 2.23-2.15 (dd, J=13.1, 8.1 Hz, 0.5H),2.06-1.79 (m, 2.5H), 1.77-1.68 (m, 1H), 1.55-1.47 (m, 2H).

Example 191(±)-(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-5. MS (ESI) mass calcd. for C₂₂H₂₁F₃N₆O₂, 458.2; m/zfound 459.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.38-8.32 (s, 0.3H), 8.26-8.19 (s,0.7H), 7.93-7.87 (s, 1.3H), 7.87-7.80 (s, 0.7H), 7.60-7.53 (m, 0.4H),7.49-7.43 (d, J=2.5 Hz, 0.4H), 7.40-7.26 (m, 2.7H), 7.00-6.93 (dd,J=8.5, 2.5 Hz, 0.4H), 6.90-6.80 (d, J=8.4 Hz, 0.7H), 6.43-6.35 (d, J=8.7Hz, 0.4H), 6.12-6.04 (d, J=8.8 Hz, 0.7H), 5.77-5.67 (m, 0.3H), 4.84-4.79(m, 0.7H), 4.74-4.68 (m, 0.3H), 4.36-4.15 (m, 1H), 4.02-3.95 (m, 1H),3.94-3.87 (s, 1H), 3.87-3.81 (s, 2H), 2.20-2.11 (dd, J=13.0, 8.0 Hz,0.7H), 2.07-1.99 (dd, J=12.9, 7.6 Hz, 0.3H), 1.99-1.83 (s, 2H),1.79-1.34 (m, 3H).

Example 192(±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-6. MS (ESI) mass calcd. for C₂₃H₁₉F₄N₅O, 457.2; m/z found458.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.91-8.76 (m, 2H), 8.36-8.18 (m, 1H),7.68-7.52 (m, 1H), 7.40-7.27 (m, 3H), 7.24-7.14 (m, 2H), 6.29-6.15 (m,1H), 4.78-4.66 (t, J=4.9 Hz, 1H), 4.44-4.30 (m, 1H), 4.16-4.02 (d, J=5.0Hz, 1H), 2.19-2.11 (dd, J=12.9, 8.2 Hz, 1H), 2.08-1.97 (m, 1H),1.97-1.85 (m, 1H), 1.77-1.60 (m, 2H), 1.54-1.49 (m, 1H).

Example 193(±)-((3-fluoro-2-methoxyphenyl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₁₉F₄N₃O₂,409.1; m/z found 410.4 [M+H]⁺. ¹H NMR (MeOD): 8.39 (s, 0.3H), 8.18 (s,0.7H), 7.69 (dd, J=8.9, 2.3 Hz, 0.3H), 7.60 (dd, J=8.9, 2.4 Hz, 0.7H),7.36 (ddd, J=11.7, 7.6, 2.1 Hz, 0.3H), 7.30-7.05 (m, 2.3H), 7.01 (d,J=7.6 Hz, 0.7H), 6.85-6.73 (m, 0.7H), 6.68 (d, J=8.8 Hz, 0.3H), 6.59 (d,J=8.9 Hz, 0.7H), 4.66 (br s, 0.7H), 4.54 (d, J=4.8 Hz, 0.3H), 4.00-3.90(m, 0.3H), 3.89-3.77 (m, 3.7H), 3.75 (t, J=4.3 Hz, 0.3H), 3.64 (br s,0.7H), 2.08-1.91 (m, 1H), 1.80-1.37 (m, 5H).

Example 194(±)-(3-ethoxy-6-methylpyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-8. MP=147° C. ¹H NMR (DMSO-D₆): 8.38 (s, 0.3H), 8.16 (s,0.7H), 7.68 (dd, J=8.9, 2.3 Hz, 0.3H), 7.59 (dd, J=8.9, 2.4 Hz, 0.7H),7.46 (d, J=8.6 Hz, 0.3H), 7.36-7.18 (m, 2H), 7.05 (d, J=8.6 Hz, 0.7H),6.71 (d, J=8.9 Hz, 0.3H), 6.57 (d, J=8.9 Hz, 0.7H), 4.65 (br s, 0.7H),4.55 (d, J=2.8 Hz, 0.3H), 4.13-3.84 (m, 2.3H), 3.83-3.72 (m, 0.7H), 3.67(d, J=3.5 Hz, 1H), 2.41 (s, 0.9H), 2.16 (s, 2.1H), 2.04-1.91 (m, 1H),1.80-1.37 (m, 5H), 1.31-1.19 (m, 3H).

Example 195(±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-9. MS (ESI) mass calcd. for C₂₃H₂₁F₃N₆O, 454.2; m/z found455 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.95-8.81 (m, 2H), 8.37 (s, 0.3H), 8.32(d, J=8.0 Hz, 0.3H), 8.25-8.13 (m, 1.4H), 7.68 (dd, J=8.8, 2.1 Hz,0.3H), 7.60 (dd, J=8.9, 2.2 Hz, 0.7H), 7.52-7.39 (m, 2H), 7.30 (d, J=8.1Hz, 0.7H), 7.25 (d, J=3.7 Hz, 0.3H), 6.75 (d, J=8.8 Hz, 0.3H), 6.54 (d,J=8.9 Hz, 0.7H), 4.61 (t, J=4.2 Hz, 0.7H), 4.51 (d, J=4.2 Hz, 0.3H),4.01-3.82 (m, 2H), 2.58 (s, 0.9H), 2.24 (s, 2.1H), 2.07-1.95 (m, 1H),1.86-1.32 (m, 5H).

Example 196(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-1. MS (ESI) mass calcd. for C₂₁H₁₉F₃N₆O, 428.2; m/z found409.2 [M+H]⁺. ¹H NMR (MeOD): 8.38 (s, 0.3H), 8.16 (s, 0.7H), 8.08 (s,2H), 7.85 (d, J=7.2 Hz, 0.3H), 7.74-7.53 (m, 3H), 7.46-7.35 (m, 1.3H),7.31 (d, J=6.1 Hz, 0.7H), 7.14 (t, J=7.5 Hz, 0.7H), 6.68 (d, J=8.9 Hz,0.3H), 6.62 (d, J=8.9 Hz, 0.7H), 4.57 (t, J=4.5 Hz, 0.7H), 4.41 (d,J=4.8 Hz, 0.3H), 4.04-3.95 (m, 0.3H), 3.88-3.76 (m, 1H), 3.55 (br s,0.7H), 1.97 (dd, J=12.7, 8.0 Hz, 1H), 1.79-1.23 (m, 5H).

Example 197(±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-2H-1,2,3-triazol-2-yl)phenyl)methanone

Step A: (±)-tert-butyl2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To a microwave vial was weighed intermediate B-6 (210 mg, 1 mmol),2-chloro-4,6-dimethylpyrimidine (212 mg, 1.5 mmol), sodium tert-butoxide(142 mg, 1.5 mmol), Pd(dba)₂ (28 mg, 5 mol %), Ctc-Q-Phos (44 mg, 10mol). The vial was capped, evacuated and refilled with N₂ (2×). ThenPhCH₃ (1 mL) was added and the reaction was heated at 125° C. for 4 h.The reaction allowed to cool to rt, applied directly purified via silicagel chromatography 1-7% 2M NH3/MeOH in DCM to give P1 (125 mg, 40%). MS(ESI) mass calcd. for C₁₇H₂₆N₄O₂, 318.2; m/z found 319.3 [M+H]⁺. ¹H NMR(CDCl₃): 6.31 (s, 1H), 5.18-4.94 (m, 1H), 4.35-4.13 (m, 2H), 4.08 (td,J=7.9, 3.2 Hz, 1H), 2.27 (s, 6H), 1.97 (dd, J=12.9, 7.8 Hz, 1H),1.82-1.62 (m, 2H), 1.62-1.30 (m, 12H).

Step B:(±)-N-(4,6-dimethylpyrimidin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine. Tothe title compound of step A (125 mg, 0.4 mmol) in DCM (3 mL) was addedTFA (3 mL). After starting material was consumed, the reaction wasconcentrated, neutralized with 5% Na₂CO₃ and extracted with DCM. Thecombined organics were dried (Na₂SO₄) to give the title compound thatwas used in subsequent reactions without further purification. MS (ESI)mass calcd. for C₁₂H₁₈N₄, 218.2; m/z found 219.2 [M+H]⁺.

Step C:(±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-10 and (1S,2R,4R)—N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-aminewith the title compound of step B. MS (ESI) mass calcd. for C₂₁H₂₂FN₇O,407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.23-7.67 (m, 2.5H),7.54-6.93 (m, 2.5H), 6.40-6.19 (m, 1H), 4.89-4.65 (m, 1H), 4.41-3.66 (m,2H), 2.39-1.34 (m, 12H).

Example 198(±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 197 substituting intermediate A-10 withintermediate A-11. MS (ESI) mass calcd. for C₂₁H₂₂FN₇O, 407.2; m/z found408.2 [M+H]⁺.

Example 199(±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 197 substituting intermediate A-10 withintermediate A-12. MS (ESI) mass calcd. for C₂₁H₂₂FN₇O, 407.2; m/z found408.2 [M+H]⁺. ¹H NMR (MeOD): 8.23-7.33 (m, 4H), 7.22-6.75 (m, 1H),6.42-6.21 (m, 1H), 4.91-4.73 (m, 1H), 4.44-4.01 (m, 1H), 3.97-3.71 (m,1H), 2.41-1.30 (m, 12H).

Example 200(±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 187 substituting2-chloro-5-(trifluoromethyl)pyridine with2-chloro-4,6-dimethylpyrimidine and intermediate A-21 with intermediateA-9. MS (ESI) mass calcd. for C₂₃H₂₅N70, 415.2; m/z found 416 [M+H]⁺. ¹HNMR (DMSO-D₆): 9.05 (d, J=4.9 Hz, 0.6H), 8.90 (d, J=4.9 Hz, 1.4H), 8.37(d, J=8.1 Hz, 0.3H), 8.28 (d, J=8.0 Hz, 0.7H), 7.57-7.45 (m, 1.3H), 7.41(d, J=8.1 Hz, 0.7H), 7.09 (d, J=7.8 Hz, 0.7H), 6.46 (s, 0.3H), 6.43-6.29(m, 1H), 4.62 (br s, 0.7H), 4.51 (d, J=4.4 Hz, 0.3H), 4.15-3.97 (m, 1H),3.97-3.92 (m, 0.3H), 3.89 (d, J=3.7 Hz, 0.7H), 2.59 (s, 0.9H), 2.50 (s,2.1H), 2.26 (s, 1.8H), 2.14 (s, 4.2H), 2.05 (dd, J=12.5, 7.6 Hz, 1H),1.99-1.37 (m, 5H).

Example 201(±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 200 substituting intermediate A-9 withintermediate A-21. MP=171.9° C. 1H NMR (DMSO-D₆): 8.28-8.17 (m, 1.2H),8.17-8.09 (m, 1.8H), 7.57 (d, J=8.4 Hz, 0.4H), 7.46 (d, J=8.4 Hz, 0.6H),6.89 (d, J=7.0 Hz, 0.6H), 6.46 (s, 0.4H), 6.42 (d, J=7.5 Hz, 0.4H), 6.35(s, 0.6H), 4.59 (t, J=4.2 Hz, 0.6H), 4.50 (d, J=4.9 Hz, 0.4H), 4.08 (td,J=7.8, 3.0 Hz, 0.4H), 4.00-3.86 (m, 1.6H), 2.60 (s, 1.2H), 2.45 (s,1.8H), 2.26 (s, 2.4H), 2.15 (s, 3.6H), 1.97 (ddd, J=16.3, 12.6, 7.9 Hz,1H), 1.83-1.35 (m, 5H).

Example 202(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 200 substituting intermediate A-9 withintermediate A-1. MP=154.2° C. 1H NMR (DMSO-D₆): 8.12 (s, 1H), 8.07 (s,1H), 7.85 (d, J=7.7 Hz, 0.5H), 7.77 (d, J=6.8 Hz, 0.5H), 7.72-7.61 (m,1H), 7.58 (dd, J=10.7, 4.2 Hz, 0.5H), 7.49-7.39 (m, 1H), 7.15 (t, J=7.5Hz, 0.5H), 6.99 (d, J=6.1 Hz, 0.5H), 6.87 (br s, 0.5H), 6.43 (s, 0.5H),6.33 (s, 0.5H), 4.51 (t, J=4.1 Hz, 0.5H), 4.37 (d, J=3.9 Hz, 0.5H),4.12-3.97 (m, 0.5H), 3.88-3.72 (m, 1H), 3.68 (d, J=4.4 Hz, 0.5H), 2.24(s, 3H), 2.15 (s, 3H), 1.97-1.21 (m, 6H).

Example 203(±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6-methylpyridin-2-yl)methanone

Prepared analogous to Example 200 substituting intermediate A-9 withintermediate A-8. MS (ESI) mass calcd. for C₂₁H₂₇N₅O₂, 381.2; m/z found382.5 [M+H]⁺. MP=137.8° C. ¹H NMR (DMSO-D₆): 7.20-7.01 (m, 2H), 6.45 (d,J=8.5 Hz, 0.7H), 6.31 (s, 0.3H), 6.24 (s, 0.7H), 5.31 (d, J=8.6 Hz,0.3H), 4.91 (t, J=4.5 Hz, 0.7H), 4.80 (d, J=5.1 Hz, 0.3H), 4.32-4.14 (m,1.7H), 4.14-3.98 (m, 1.3H), 3.80 (t, J=4.7 Hz, 0.3H), 3.75 (d, J=4.6 Hz,0.7H), 2.53 (s, 2.1H), 2.49 (s, 0.9H), 2.26 (s, 1.8H), 2.22 (s, 4.2H),2.20-2.08 (m, 1H), 2.05-1.49 (m, 5H), 1.48-1.40 (m, 3H).

Example 204(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Tointermediate B-6 (500 mg, 2.4 mmol) in dry DMA (7 mL) was added K₂CO₃(650 mg, 4.7 mmol) and 2-chloroquinoxaline (580 mg, 3.5 mmol). Afterheating at 80° C. for 48 h, the mixture was cooled to rt and saturatedNaHCO₃ (aq) was added. The mixture was extracted with EtOAc (3×). Thecombined organics were washed with brine and dried (MgSO₄). Purificationvia silica gel chromatography (0-25% EtOAc in heptanes) gave the titlecompound. MS (ESI) mass calcd. for C₁₉H₂₄N₄O₂, 340.2; m/z found 341.0[M+H]⁺.

Step B: N-((±)-7-azabicyclo[2.2.1]heptan-2-yl)quinoxalin-2-aminehydrochloride. To the title compound from step A (343 mg, 1 mmol) in1,4-dioxane (10 mL) was added 6N HCl in iPrOH (1 mL). The reaction washeated to 70° C. for 2 h, cooled to rt, concentrated and used withoutfurther purification in subsequent steps.

Step C:(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 187 substituting intermediate A-21 withintermediate A-1 and(±)-N-(5-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-aminehydrochloride with the title compound from step B. MS (ESI) mass calcd.for C₂₃H₂₁N70, 411.2; m/z found 412 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.38 (s,0.3H), 8.31 (s, 0.7H), 8.08 (s, 2H), 7.88-7.73 (m, 1.3H), 7.72-7.20 (m,7H), 7.14-7.04 (m, 0.7H), 4.60 (t, J=4.4 Hz, 0.7H), 4.54 (d, J=4.7 Hz,0.3H), 4.15-4.03 (m, 0.3H), 3.97-3.87 (m, 0.7H), 3.82 (t, J=3.9 Hz,0.3H), 3.65 (d, J=3.2 Hz, 0.7H), 2.12-1.96 (m, 1H), 1.84-1.28 (m, 5H).

Example 205(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 204 substituting with intermediate A-1with intermediate A-21. MP=260.8° C. ¹H NMR (DMSO-D₆): 8.44 (s, 0.3H),8.32 (s, 0.7H), 8.19 (d, J=8.4 Hz, 0.3H), 8.13 (s, 2H), 7.96 (d, J=8.3Hz, 0.7H), 7.83-7.72 (m, 1H), 7.68-7.27 (m, 4.3H), 7.19 (d, J=8.4 Hz,0.7H), 4.64 (br s, 1H), 4.06-3.86 (m, 2H), 2.61 (s, 0.9H), 2.09 (s,2.1H), 2.06-1.99 (m, 1H), 1.88-1.62 (m, 2H), 1.62-1.38 (m, 3H).

Example 206(±)-(3-fluoro-2-methoxyphenyl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 204 substituting intermediate A-1 with3-fluoro-2-methoxybenzoic acid. MP=179.2° C. ¹H NMR (DMSO-D₆): 8.38 (s,0.3H), 8.27 (s, 0.7H), 7.80 (d, J=8.0 Hz, 0.3H), 7.73 (d, J=8.0 Hz,0.7H), 7.65-7.52 (m, 1.4H), 7.52-7.28 (m, 2.7H), 7.28-7.15 (m, 0.7H),7.09 (d, J=7.6 Hz, 0.7H), 6.96 (ddd, J=11.7, 8.2, 1.4 Hz, 0.7H), 6.75(td, J=7.9, 4.8 Hz, 0.7H), 4.75-4.63 (m, 1H), 4.11-4.01 (m, 0.4H),3.99-3.90 (m, 0.7H), 3.86 (br s, 0.9H), 3.83-3.73 (m, 2.1H), 2.06 (dt,J=16.7, 8.4 Hz, 1H), 1.87-1.45 (m, 6H).

Example 207(±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 204 substituting with intermediate A-1with intermediate A-8. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/zfound 404 [M+H]⁺. MP=184.9 C. ¹H NMR (DMSO-D₆): 8.41 (s, 0.3H), 8.26 (s,0.7H), 7.79 (d, J=8.1 Hz, 0.3H), 7.72 (d, J=8.0 Hz, 0.7H), 7.64-7.53 (m,1.7H), 7.50-7.22 (m, 2.9H), 7.18 (d, J=8.6 Hz, 0.7H), 6.86 (d, J=8.6 Hz,0.7H), 4.68 (br s, 1H), 4.12-3.83 (m, 3H), 3.79 (d, J=4.1 Hz, 0.7H),3.71 (br s, 0.3H), 2.41 (s, 0.9H), 2.11-1.96 (m, 3.1H), 1.89-1.42 (m,5H), 1.25 (t, J=6.9 Hz, 3H).

Example 208(±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 204 substituting with intermediate A-1with intermediate A-9. MS (ESI) mass calcd. for C₂₅H₂₃N70, 437.2; m/zfound 438 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.93-8.82 (m, 2H), 8.46 (s, 0.3H),8.33 (d, J=8.1 Hz, 0.3H), 8.27 (s, 0.7H), 8.14 (d, J=8.0 Hz, 0.7H),7.81-7.26 (m, 6.3H), 7.17 (d, J=8.1 Hz, 0.7H), 4.66 (br s, 1H),4.06-3.94 (m, 2H), 2.60 (s, 0.9H), 2.13-2.01 (m, 3.1H), 1.92-1.36 (m,5H).

Example 209(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((6-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A:(±)-tert-butyl-2-((6-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To 2-chloro-6-(trifluoromethyl)pyridine (113 mg, 0.6 mmol) in THF (3 mL)was added sodium tert-butoxide (120 mg, 1.2 mmol), Xanphos (26 mg, 7 mol%) and Pd₂(dba)₃ (23 mg, 4 mol %) at rt while N₂ was bubbled through thesolution. After 10 minutes, intermediate B-6 (132 mg, 0.6 mmol) wasadded. The reaction mixture was heated at 90° C. for 3 h. After allowingto cool to rt, saturated NaHCO₃ (aq) the mixture extracted with EtOAc(2×). The combined organics were dried (MgSO₄). Purification via silicagel chromatography (0-7% EtOAc in heptane) gave the title compound. MS(ESI) mass calcd. for C₁₇H₂₂F₃N₃O₂, 357.2; m/z found 358.4 [M+H]⁺.

Step B:(±)-N-(6-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-aminehydrochloride. Prepared analogous to Example 204 substituting(±)-tert-butyl2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptane-7-carboxylate withthe title compound of step A.

Step C:(±)-tert-butyl-2-((6-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to Example 204 substitutingN-((±)-7-azabicyclo[2.2.1]heptan-2-yl)quinoxalin-2-amine hydrochloridewith the title compound of step B. MS (ESI) mass calcd. for C₂₁H₁₉F₃N₆O,428.2; m/z found 429. [M+H]⁺. MP=96.8° C. ¹H NMR (DMSO-D₆): 8.07 (s,2H), 7.85 (d, J=7.9 Hz, 0.3H), 7.74-7.51 (m, 2.7H), 7.46-7.36 (m, 1.3H),7.17-6.94 (m, 2H), 6.86 (d, J=7.2 Hz, 0.7H), 6.82 (d, J=8.6 Hz, 0.3H),6.74 (d, J=8.4 Hz, 0.7H), 4.55 (t, J=4.5 Hz, 0.7H), 4.41 (d, J=4.6 Hz,0.3H), 3.94-3.84 (m, 0.3H), 3.84-3.71 (m, 1H), 3.61 (d, J=4.6 Hz, 0.7H),1.96 (dd, J=12.6, 8.0 Hz, 1H), 1.80-1.21 (m, 5H).

Example 210(±)-((2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with2-chloro-4-(trifluoromethyl)pyridine. MP=153.5° C. MS (ESI) mass calcd.for C₂₁H₁₉F₃N₆O, 428.2; m/z found 429 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.27 (d,J=5.3 Hz, 0.3H), 8.12-7.99 (m, 2.7H), 7.85 (d, J=7.9 Hz, 0.3H),7.72-7.54 (m, 1.6H), 7.50-7.33 (m, 1.4H), 7.13-6.92 (m, 2H), 6.82 (d,J=12.6 Hz, 0.3H), 6.78 (s, 0.7H), 6.67 (d, J=5.3 Hz, 0.7H), 4.56 (t,J=4.5 Hz, 0.7H), 4.41 (d, J=4.6 Hz, 0.3H), 4.04-3.93 (m, 0.3H),3.86-3.72 (m, 1H), 3.52 (br s, 0.7H), 1.96 (dd, J=12.6, 8.0 Hz, 1H),1.78-1.17 (m, 5H).

Example 211(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-chloropyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with 5-chloro-2-iodopyridine. MS(ESI) mass calcd. for C₂₀H₁₉ClN₆O, 394.1; m/z found 395 [M+H]⁺.MP=157.0° C. ¹H NMR (DMSO-D₆): 8.14-7.99 (m, 2.3H), 7.87-7.79 (m, 1H),7.71-7.52 (m, 1.7H), 7.52-7.36 (m, 2.6H), 7.23-7.11 (m, 0.7H), 6.80 (d,J=6.4 Hz, 0.7H), 6.58 (d, J=9.0 Hz, 0.3H), 6.52 (d, J=8.9 Hz, 0.7H),4.53 (t, J=4.6 Hz, 0.7H), 4.37 (d, J=4.6 Hz, 0.3H), 3.92-3.82 (m, 0.3H),3.81-3.68 (m, 1H), 3.52 (d, J=4.3 Hz, 0.7H), 1.94 (dd, J=12.5, 8.1 Hz,1H), 1.73-1.22 (m, 5H).

Example 212(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((6-(trifluoromethyl)pyridazin-3-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with3-chloro-6-(trifluoromethyl)pyridazine. MP=134.0° C. MS (ESI) masscalcd. for C₂₀H₁₈F₃N₇O, 429.2; m/z found 430 [M+H]⁺. ¹H NMR (DMSO-D₆):8.08 (s, 1.4H), 8.07 (s, 0.6H), 7.85 (d, J=7.8 Hz, 0.3H), 7.77-7.46 (m,3.6H), 7.44-7.31 (m, 1.4H), 7.20-7.09 (m, 0.7H), 7.06 (d, J=9.4 Hz,0.3H), 6.98 (d, J=9.3 Hz, 0.7H), 4.59 (t, J=4.4 Hz, 0.7H), 4.48 (d,J=4.7 Hz, 0.3H), 3.97-3.87 (m, 0.7H), 3.81 (t, J=4.0 Hz, 0.3H),3.58-3.56 (m, 1H), 2.01 (dd, J=12.9, 8.0 Hz, 1H), 1.82-1.18 (m, 5H).

Example 213(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-methoxypyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with 2-chloro-5-methoxypyridine. MS(ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391 [M+H]⁺. MP=174.0°C. ¹H NMR (DMSO-D₆): 8.31 (s, 0.3H), 8.13-8.02 (m, 2H), 7.84 (d, J=8.0Hz, 0.3H), 7.79 (d, J=3.0 Hz, 0.3H), 7.71-7.61 (m, 1.3H), 7.60-7.53 (m,1H), 7.50-7.37 (m, 1.4H), 7.22-7.04 (m, 1.7H), 6.52 (d, J=9.0 Hz, 0.3H),6.46 (d, J=9.0 Hz, 0.7H), 6.21 (d, J=6.9 Hz, 0.7H), 4.52 (t, J=4.5 Hz,0.7H), 4.37 (d, J=4.5 Hz, 0.2H), 3.90-3.79 (m, 0.3H), 3.79-3.68 (m,1.9H), 3.64 (s, 2.1H), 3.57 (d, J=4.0 Hz, 0.7H), 1.98-1.84 (m, 1H),1.76-1.21 (m, 5H).

Example 214(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-methylpyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with 2-chloro-5-methylpyridine. MS(ESI) mass calcd. for C₂₁H₂₂N₆O, 374.2; m/z found 375.2 [M+H]⁺. ¹H NMR(DMSO-D₆): 8.32 (s, 0.7H), 8.09 (s, 0.6H), 8.07 (s, 1.4H), 7.89-7.80 (m,0.6H), 7.72-7.53 (m, 2.1H), 7.52-7.37 (m, 1.3H), 7.27 (dd, J=8.5, 2.2Hz, 0.3H), 7.23-7.11 (m, 1.3H), 6.47 (d, J=8.5 Hz, 0.3H), 6.41 (d, J=8.2Hz, 0.7H), 6.35 (d, J=6.9 Hz, 0.7H), 4.53 (t, J=4.5 Hz, 0.7H), 4.37 (d,J=4.4 Hz, 0.3H), 3.95-3.84 (m, 0.3H), 3.84-3.70 (m, 1H), 3.56 (d, J=4.3Hz, 0.7H), 2.12 (s, 0.9H), 2.04 (s, 2.1H), 1.99-1.86 (m, 1H), 1.78-1.24(m, 5H).

Example 215(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(pyridin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with 2-iodopyridine. MS (ESI) masscalcd. for C₂₀H₂₀N₆O, 360.2; m/z found 361 [M+H]⁺. MP=167.9° C. ¹H NMR(DMSO-D₆): 8.12-8.00 (m, 2.3H), 7.88-7.79 (m, 1H), 7.73-7.53 (m, 1.5H),7.50-7.28 (m, 2.5H), 7.13 (t, J=7.4 Hz, 0.7H), 6.63-6.37 (m, 3H), 4.54(t, J=4.5 Hz, 0.7H), 4.39 (d, J=4.4 Hz, 0.3H), 3.92 (td, J=7.5, 3.2 Hz,0.3H), 3.86-3.73 (m, 1H), 3.58 (d, J=4.3 Hz, 0.7H), 2.02-1.86 (m, 1H),1.78-1.23 (m, 5H).

Example 216(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-chlorobenzo[d]oxazol-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-((5-chlorobenzo[d]oxazol-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-6 (116 mg, 0.6 mmol) in 1,4-dioxane (3 mL) was addedDIPEA (190 μL, 1.1 mmol) and 5-chloro-2-(methylsulfinyl)benzo[d]oxazole(235 mg, 1.1 mmol). After heating at 80° C. for 4 h, the mixture wascooled to rt and saturated NaHCO₃ (aq) was added. The aqueous layer wasextracted with EtOAc (3×). The combined organics were dried (MgSO₄).Purification via silica gel chromatography (0-10% EtOAc in hexanes) gavethe title compound (130 mg, 66%). MS (ESI) mass calcd. for C₁₈H₂₂ClN₃O₃,363.1; m/z found 364.0 [M+H]⁺.

Step B:N-((±)-7-azabicyclo[2.2.1]heptan-2-yl)-5-chlorobenzo[d]oxazol-2-aminehydrochloride. Prepared analogous to Example 209 substituting(±)-tert-butyl-2-((6-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylatewith the title compound of step A. MS (ESI) mass calcd. for C₁₃H₁₄ClN₃O,263.1; m/z found 264.0 [M+H]⁺.

Step C:(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-chlorobenzo[d]oxazol-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 209 substituting(±)-N-(6-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-aminehydrochloride with the title compound of step B. MS (ESI) mass calcd.for C₂₂H₁₉ClN₆O₂, 434.1; m/z found 435 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.20(d, J=5.6 Hz, 1H), 8.13-8.05 (m, 2H), 7.85 (d, J=7.4 Hz, 0.3H), 7.76 (d,J=7.3 Hz, 0.3H), 7.72-7.55 (m, 1.3H), 7.53-7.44 (m, 0.7H), 7.44-7.29 (m,2H), 7.24 (d, J=2.1 Hz, 0.7H), 7.16-7.08 (m, 0.7H), 7.08-6.98 (m, 1H),4.66-4.47 (m, 1H), 3.97-3.86 (m, 0.3H), 3.82 (t, J=3.9 Hz, 0.3H),3.79-3.66 (m, 1.4H), 2.07-1.92 (m, 1H), 1.88-1.22 (m, 5H).

Example 217(±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with 5-bromo-2-iodopyridine andintermediate A-1 with intermediate A-9. MS (ESI) mass calcd. forC₂₂H₂₁BrN₆O, 464.1; m/z found 466 [M+H]⁺. MP=221.8° C. ¹H NMR (DMSO-D₆):8.96-8.78 (m, 2H), 8.32 (d, J=8.0 Hz, 0.3H), 8.19 (d, J=8.0 Hz, 0.7H),8.10 (d, J=2.4 Hz, 0.3H), 7.93 (d, J=2.4 Hz, 0.7H), 7.56 (dd, J=8.9, 2.5Hz, 0.3H), 7.51-7.39 (m, 2H), 7.33 (d, J=8.1 Hz, 0.7H), 6.93 (d, J=7.1Hz, 0.7H), 6.66 (d, J=5.6 Hz, 0.3H), 6.61 (d, J=9.0 Hz, 0.3H), 6.36 (d,J=8.9 Hz, 0.7H), 4.59 (t, J=4.1 Hz, 0.7H), 4.47 (d, J=4.3 Hz, 0.3H),3.96-3.75 (m, 2H), 2.58 (s, 0.9H), 2.31 (s, 2.1H), 2.07-1.91 (m, 1H),1.88-1.30 (m, 5H).

Example 218(±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-methoxyphenyl)methanone

Prepared analogous to Example 217 substituting intermediate A-9 with3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₁₉H₁₉BrFN₃O₂,419.1; m/z found 420.1 [M+H]⁺. MP=175.2° C. ¹H NMR (DMSO-D₆): 8.10 (d,J=2.4 Hz, 0.3H), 7.90 (d, J=2.4 Hz, 0.7H), 7.56 (dd, J=8.9, 2.5 Hz,0.3H), 7.47 (dd, J=8.9, 2.5 Hz, 0.7H), 7.34 (ddd, J=11.7, 7.5, 2.3 Hz,0.3H), 7.24-7.08 (m, 1.3H), 7.02 (d, J=7.6 Hz, 0.7H), 6.87-6.66 (m,1.7H), 6.54 (d, J=8.9 Hz, 0.3H), 6.46 (d, J=8.9 Hz, 0.7H), 4.63 (br s,0.7H), 4.50 (d, J=4.8 Hz, 0.3H), 3.88-3.68 (m, 4.3H), 3.58 (d, J=2.9 Hz,0.7H), 2.05-1.87 (m, 1H), 1.78-1.20 (m, 5H).

Example 219(±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6-methylpyridin-2-yl)methanone

Prepared analogous to Example 217 substituting intermediate A-9 withintermediate A-8. MS (ESI) mass calcd. for C₂₀H₂₃BrN₄O₂, 430.1; m/zfound 431.1 [M+H]⁺. MP=134.5° C. ¹H NMR (DMSO-D₆): 8.10 (d, J=2.4 Hz,0.3H), 7.88 (d, J=2.4 Hz, 0.7H), 7.55 (dd, J=8.9, 2.5 Hz, 0.3H),7.50-7.41 (m, 1H), 7.30 (d, J=8.6 Hz, 0.7H), 7.24 (d, J=8.6 Hz, 0.3H),7.08 (d, J=8.6 Hz, 0.7H), 6.76 (d, J=5.7 Hz, 0.7H), 6.63 (d, J=5.3 Hz,0.3H), 6.57 (d, J=8.9 Hz, 0.3H), 6.43 (d, J=8.9 Hz, 0.7H), 4.62 (br s,0.7H), 4.51 (d, J=2.8 Hz, 0.3H), 4.13-3.88 (m, 2H), 3.83-3.73 (m, 0.3H),3.72-3.61 (m, 1H), 3.59 (d, J=3.5 Hz, 0.7H), 2.39 (s, 0.9H), 2.21 (s,2.1H), 2.02-1.85 (m, 1H), 1.75-1.33 (m, 5H), 1.25 (td, J=6.9, 3.6 Hz,3H).

Example 220(±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 217 substituting intermediate A-9 withintermediate A-21. MS (ESI) mass calcd. for C₂₀H₂₀BrN₇O, 453.1; m/zfound 454.1 [M+H]⁺. MP=214.9° C. ¹H NMR (DMSO-D₆): 8.18 (d, J=8.4 Hz,0.3H), 8.14-8.09 (m, 2.3H), 8.05 (d, J=8.4 Hz, 0.7H), 7.93 (d, J=2.4 Hz,0.7H), 7.62-7.53 (m, 0.6H), 7.50 (dd, J=8.9, 2.5 Hz, 0.7H), 7.40 (d,J=8.4 Hz, 0.7H), 6.76 (d, J=6.3 Hz, 0.7H), 6.61 (d, J=8.9 Hz, 0.3H),6.52 (d, J=5.7 Hz, 0.3H), 6.45 (d, J=8.9 Hz, 0.7H), 4.58 (t, J=4.5 Hz,0.7H), 4.47 (d, J=4.8 Hz, 0.3H), 3.91 (t, J=4.3 Hz, 0.3H), 3.88-3.68 (m,1.7H), 2.60 (s, 0.9H), 2.31 (s, 2.1H), 2.03-1.90 (m, 1H), 1.81-1.29 (m,5H).

Example 221(±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 220 substituting intermediate A-21 withintermediate A-1. MP=167.1° C. ¹H NMR (DMSO-D₆): 8.75 (s, 0.4H), 8.70(s, 0.4H), 8.66 (s, 0.6H), 8.53 (s, 0.6H), 8.12-8.03 (m, 2.6H), 7.86 (d,J=7.3 Hz, 0.4H), 7.80 (d, J=7.2 Hz, 0.4H), 7.72-7.54 (m, 1.6H),7.48-7.34 (m, 1.4H), 7.16 (t, J=7.4 Hz, 0.6H), 4.56 (br s, 0.6H), 4.41(d, J=4.3 Hz, 0.4H), 4.08 (dd, J=11.1, 6.8 Hz, 0.4H), 3.90-3.75 (m, 1H),3.61 (d, J=4.3 Hz, 0.6H), 2.01-1.27 (m, 6H).

Example 222(±)-(3-fluoro-2-methoxyphenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 221 substituting intermediate A-1 with3-fluoro-2-methoxybenzoic acid. ¹H NMR (DMSO-D₆): 8.72 (br d, J=22.6 Hz,0.8H), 8.58 (br d, J=24.1 Hz, 1.2H), 8.12 (br d, J=5.6 Hz, 0.4H), 7.99(br d, J=5.0 Hz, 0.6H), 7.45-7.23 (m, 0.8H), 7.26-7.06 (m, 1.2H), 6.97(d, J=7.5 Hz, 0.6H), 6.90-6.72 (m, 0.6H), 4.65 (br s, 0.6H), 4.53 (d,J=4.8 Hz, 0.4H), 3.97 (dd, J=11.4, 6.0 Hz, 0.4H), 3.84 (s, 1.2H),3.93-3.71 (m, 1H), 3.78 (s, 1.8H), 3.69 (br d, J=2.9 Hz, 0.6H),2.06-1.35 (m, 6H)

Example 223(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 221 substituting intermediate A-1 withintermediate A-21. ¹H NMR (DMSO-D₆): 8.74 (br d, J=12.1 Hz, 0.4H), 8.63(br d, J=13.2 Hz, 1.2H), 8.26-8.01 (m, 3.4H), 7.61 (dd, J=21.8, 7.4 Hz,0.4H), 7.43 (d, J=8.4 Hz, 0.6H), 4.61 (br s, 0.6H), 4.55 (d, J=5.0 Hz,0.4H), 4.11-4.01 (m, 0.4H), 4.02-3.93 (m, 1H), 3.88 (dd, J=10.1, 6.1 Hz,0.6H), 3.22-3.06 (m, 1H), 2.60 (s, 1H), 2.30 (s, 2H), 2.06-1.34 (n, 6H).

Example 224(±)-(3-ethoxy-6-methylpyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 221 substituting intermediate A-1 withintermediate A-8. ¹H NMR (DMSO-D₆): 8.79 (br d, J=22.9 Hz, 0.6H), 8.65(br d, J=17.4 Hz, 1.4H), 8.21 (d, J=5.3 Hz, 0.7H), 7.92 (d, J=5.2 Hz,0.3H), 7.52 (d, J=8.6 Hz, 0.3H), 7.42 (d, J=8.6 Hz, 0.7H), 7.32 (d,J=8.6 Hz, 0.3H), 7.18 (d, J=8.6 Hz, 0.7H), 4.71 (br s, 0.7H), 4.64 (brd, J=4.7 Hz, 0.3H), 4.23-3.93 (m, 2.5H), 3.93-3.78 (m, 1.4H), 3.78-3.55(m, 1.7H), 3.31-3.07 (m, 1.4H), 2.47 (s, 1H), 2.31 (s, 2H), 2.06-1.40(m, 6H).

Example 225(±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 221 substituting intermediate A-1 withintermediate A-9. MP=203° C. MS (ESI) mass calcd. for C₂₂H₂₀F₃N₇O,455.2; m/z found 427.5 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.94 (d, J=4.9 Hz,0.4H), 8.89 (d, J=4.9 Hz, 1.6H), 8.77 (s, 0.2H), 8.71 (s, 0.2H), 8.61(s, 1.4H), 8.36 (d, J=8.1 Hz, 0.2H), 8.24 (d, J=7.9 Hz, 1.8H), 7.72 (d,J=6.0 Hz, 0.2H), 7.54-7.44 (m, 1.2H), 7.38 (d, J=8.1 Hz, 0.8H), 4.64 (brs, 0.8H), 4.58 (d, J=4.6 Hz, 0.2H), 4.06-3.90 (m, 2H), 2.60 (s, 0.6H),2.35 (s, 2.4H), 2.11-1.73 (m, 4H), 1.62-1.35 (m, 2H).

Example 226(±)-(3-fluoro-2-methoxyphenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 222 substituting intermediate B-6 withintermediate B-7. MS (ESI) mass calcd. for C₁₉H₁₈F₄N₄O₂, 410.2; m/zfound 411.3 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.75 (s, 0.5H), 8.68 (s, 0.5H),8.61 (s, 0.5H), 8.57 (s, 0.5H), 8.52 (d, J=6.3 Hz, 0.5H), 8.44 (d, J=6.3Hz, 0.5H), 7.44-7.29 (m, 1H), 7.23-7.08 (m, 2H), 4.82 (t, J=3.9 Hz,0.5H), 4.58 (t, J=4.5 Hz, 0.5H), 4.34-4.12 (m, 1H), 3.94-3.81 (m, 3.5H),3.68 (t, J=4.2 Hz, 0.5H), 2.31-2.11 (m, 1H), 1.93-1.40 (m, 5H).

Example 227(±)-(3-ethoxy-6-methylpyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 224 substituting intermediate B-6 withintermediate B-7. MP=79.7° C. MS (ESI) mass calcd. for C₂₀H₂₂F₃N₅O₂,421.2; m/z found 422.4 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.76 (s, 0.5H), 8.68(s, 0.5H), 8.61 (s, 0.5H), 8.56 (s, 0.5H), 8.52 (d, J=6.4 Hz, 0.5H),8.44 (d, J=6.6 Hz, 0.5H), 7.48 (d, J=3.2 Hz, 0.5H), 7.45 (d, J=3.2 Hz,0.5H), 7.28 (d, J=3.3 Hz, 0.5H), 7.25 (d, J=3.3 Hz, 0.5H), 4.83 (t,J=4.2 Hz, 0.5H), 4.59 (t, J=4.3 Hz, 0.5H), 4.40-4.29 (m, 0.5H),4.28-4.19 (m, 0.5H), 4.16-4.01 (m, 2H), 3.79 (t, J=4.4 Hz, 0.5H), 3.61(t, J=4.6 Hz, 0.5H), 2.41 (s, 1.5H), 2.40 (s, 1.5H), 2.30-2.09 (m, 1H),1.93-1.41 (m, 5H), 1.34-1.23 (m, 3H).

Example 228(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 223 substituting intermediate B-6 withintermediate B-7. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found445.4 [M+H]⁺. MP=89.1° C. ¹H NMR (DMSO-D₆): 8.77 (s, 0.6H), 8.68 (s,0.6H), 8.61 (s, 0.4H), 8.55 (s, 0.4H), 8.51 (d, J=6.3 Hz, 0.6H), 8.44(d, J=6.3 Hz, 0.4H), 8.24-8.16 (m, 1H), 8.13 (s, 1H), 8.12 (s, 1H),7.63-7.52 (m, 1H), 4.81 (t, J=4.2 Hz, 0.6H), 4.55 (t, J=4.2 Hz, 0.4H),4.40-4.21 (m, 1H), 4.06 (t, J=4.4 Hz, 0.4H), 3.79 (t, J=4.4 Hz, 0.6H),2.61 (s, 1.2H), 2.58 (s, 1.8H), 2.34-2.20 (m, 0.6H), 2.19-2.03 (m,0.6H), 1.94-1.50 (m, 4.2H), 1.44 (dd, J=12.3, 4.6 Hz, 0.6H).

Example 229(±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 207 substituting intermediate B-6 withintermediate B-7. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found404.5 [M+H]⁺. MP=115.1° C. ¹H NMR (DMSO-D₆): 8.37 (s, 0.5H), 8.30 (s,0.5H), 7.97 (t, J=5.4 Hz, 1H), 7.80 (d, J=7.4 Hz, 0.5H), 7.75 (d, J=7.1Hz, 0.5H), 7.69-7.44 (m, 2.5H), 7.43-7.23 (m, 2.5H), 4.99 (t, J=4.4 Hz,0.5H), 4.63 (t, J=4.6 Hz, 0.5H), 4.48-4.27 (m, 1H), 4.26-4.13 (m, 2H),3.96 (t, J=4.4 Hz, 0.5H), 3.64 (t, J=4.6 Hz, 0.5H), 2.44 (s, 1.5H), 2.41(s, 1.5H), 2.39-2.26 (m, 1H), 1.98-1.37 (m, 5H), 1.36-1.28 (m, 3H).

Example 230(±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 205 substituting intermediate B-6 withintermediate B-7. MS (ESI) mass calcd. for C₂₃H₂₂N80, 426.2; m/z found427.5 [M+H]⁺. MP=152.3° C. ¹H NMR (DMSO-D₆): 8.37 (s, 0.5H), 8.28-8.20(m, 2H), 8.16-8.13 (m, 2H), 7.95 (dd, J=5.6, 3.6 Hz, 1H), 7.79 (d, J=8.1Hz, 0.5H), 7.74 (d, J=8.1 Hz, 0.5H), 7.70-7.48 (m, 2.5H), 7.41-7.23 (m,1.5H), 4.98 (t, J=4.2 Hz, 0.5H), 4.60 (t, J=4.6 Hz, 0.5H), 4.36-4.24 (m,1H), 4.19 (t, J=4.5 Hz, 0.5H), 3.81 (t, J=4.6 Hz, 0.5H), 2.67 (s, 1.5H),2.60 (s, 1.5H), 2.43-2.17 (m, 1H), 1.97-1.25 (m, 5H).

Example 231(±)-(3-fluoro-2-methoxyphenyl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 206 substituting intermediate B-6 withintermediate B-7. ¹H NMR (DMSO-D₆): 8.36 (s, 0.5H), 8.29 (s, 0.5H),8.08-7.95 (m, 1H), 7.85-7.69 (m, 1H), 7.69-7.49 (m, 1.5H), 7.49-7.27 (m,2H), 7.27-7.12 (m, 2.5H), 5.00 (t, J=4.2 Hz, 0.5H), 4.62 (t, J=4.2 Hz,0.5H), 4.43-4.17 (m, 1H), 4.11 (t, J=4.3 Hz, 0.5H), 3.95 (s, 1.5H), 3.88(s, 1.5H), 3.72 (t, J=4.5 Hz, 0.5H), 2.45-2.25 (m, 1H), 1.99-1.46 (m,4H), 1.46-1.28 (m, 1H).

Example 232(±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepare analogous to Example 220 substituting intermediate B-6 withintermediate B-7. MP=196.0° C. ¹H NMR (DMSO-D₆): 8.25-8.16 (m, 1H),8.16-8.10 (m, 2.6H), 7.90 (d, J=2.4 Hz, 0.4H), 7.63-7.53 (m, 1.6H), 7.50(dd, J=8.9, 2.5 Hz, 0.4H), 7.19 (d, J=6.0 Hz, 0.6H), 7.12 (d, J=6.1 Hz,0.4H), 6.54 (d, J=8.9 Hz, 0.6H), 6.44 (d, J=8.9 Hz, 0.4H), 4.81 (t,J=4.2 Hz, 0.6H), 4.54 (t, J=4.2 Hz, 0.4H), 4.23-4.07 (m, 1H), 4.04 (t,J=4.5 Hz, 0.4H), 3.75 (t, J=4.5 Hz, 0.6H), 2.61 (s, 1.2H), 2.58 (s,1.8H), 2.36-2.05 (m, 1H), 1.92-1.41 (m, 4H), 1.30 (dd, J=12.4, 4.4 Hz,0.4H), 1.18 (dd, J=12.2, 4.6 Hz, 0.6H).

Example 233(±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6-methylpyridin-2-yl)methanone

Prepare analogous to Example 219 substituting intermediate B-6 withintermediate B-7. MP=176.1° C. H ¹H NMR (DMSO-D₆): 8.11 (d, J=2.4 Hz,0.5H), 7.91 (d, J=2.4 Hz, 0.5H), 7.61-7.43 (m, 2H), 7.33-7.20 (m, 1.5H),7.15 (d, J=6.1 Hz, 0.5H), 6.55 (d, J=8.9 Hz, 0.5H), 6.46 (d, J=8.9 Hz,0.5H), 4.83 (t, J=4.3 Hz, 0.5H), 4.57 (t, J=4.6 Hz, 0.5H), 4.20 (d,J=5.5 Hz, 0.5H), 4.09 (dq, J=10.2, 6.9 Hz, 2.5H), 3.79 (t, J=4.3 Hz,0.5H), 3.58 (t, J=4.6 Hz, 0.5H), 2.41 (s, 1.5H), 2.40 (s, 1.5H),2.32-2.14 (m, 1H), 1.93-1.45 (m, 4H), 1.36-1.17 (m, 4H).

Example 234(±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-methoxyphenyl)methanone

Prepare analogous to Example 217 substituting intermediate B-6 withintermediate B-7. MP=144.5° C. ¹H NMR (DMSO-D₆): 8.11 (d, J=2.4 Hz,0.6H), 7.91 (d, J=2.4 Hz, 0.4H), 7.56 (dd, J=8.9, 2.5 Hz, 0.6H), 7.50(dd, J=8.9, 2.5 Hz, 0.4H), 7.43-7.30 (m, 1H), 7.27-7.05 (m, 3H), 6.54(d, J=8.9 Hz, 0.6H), 6.46 (d, J=8.9 Hz, 0.4H), 4.83 (t, J=4.3 Hz, 0.6H),4.57 (t, J=4.7 Hz, 0.4H), 4.21-3.99 (m, 1H), 3.95-3.81 (m, 3.4H), 3.66(t, J=4.7 Hz, 0.6H), 2.36-2.14 (m, 1H), 1.94-1.43 (m, 4H), 1.36-1.14 (m,1H).

Example 235(±)-((2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 210 substituting intermediate B-6 withintermediate B-7. MS (ESI) mass calcd. for C₂₁H₁₉F₃N₆O, 428.2; m/z found429 [M+H]⁺. MP=274.2° C. ¹H NMR (DMSO-D₆): 8.27 (d, J=5.2 Hz, 0.5H),8.13-8.01 (m, 2.5H), 7.89-7.80 (m, 1H), 7.73-7.61 (m, 1H), 7.61-7.51 (m,2H), 7.44 (d, J=6.1 Hz, 0.5H), 7.38 (d, J=5.9 Hz, 0.5H), 6.83-6.75 (m,1H), 6.73-6.63 (m, 1H), 4.78 (t, J=3.9 Hz, 0.5H), 4.50 (t, J=4.6 Hz,0.5H), 4.27-4.04 (m, 1H), 3.96 (t, J=4.1 Hz, 0.5H), 3.64 (t, J=4.1 Hz,0.5H), 2.40-2.21 (m, 0.5H), 2.17-1.99 (m, 0.5H), 1.88-1.32 (m, 4H), 1.27(dd, J=12.3, 4.3 Hz, 0.5H), 1.12 (dd, J=12.2, 4.5 Hz, 0.5H).

Example 236(±)-(2-((5-fluoropyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with 5-fluoro-2-iodopyridine andintermediate A-1 with A-21. MP=100.1° C. MS (ESI) mass calcd. forC₂₀H₂₀FN₇O, 393.2; m/z found 394.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.24-8.15(m, 1H), 8.12 (s, 1.2H) 8.11 (s, 0.8H), 8.00 (d, J=2.9 Hz, 0.6H), 7.80(d, J=2.8 Hz, 0.4H), 7.63-7.51 (m, 1H), 7.43-7.26 (m, 1H), 6.94 (d,J=5.9 Hz, 0.6H), 6.87 (d, J=6.0 Hz, 0.4H), 6.55 (dd, J=9.1, 3.6 Hz,0.6H), 6.45 (dd, J=9.1, 3.7 Hz, 0.4H), 4.81 (t, J=4.2 Hz, 0.6H), 4.52(t, J=4.6 Hz, 0.4H), 4.19-3.99 (m, 1.4H), 3.73 (t, J=4.6 Hz, 0.6H), 2.60(s, 1.2H), 2.58 (s, 1.8H), 2.35-2.20 (m, 0.6H), 2.19-2.05 (m, 0.4H),1.96-1.38 (m, 4H), 1.27 (dd, J=12.5, 4.2 Hz, 0.6H), 1.15 (dd, J=12.2,4.8 Hz, 0.4H).

Example 237(±)-(3-fluoro-2-methoxyphenyl)(2-((5-fluoropyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting2-chloro-6-(trifluoromethyl)pyridine with 5-fluoro-2-iodopyridine andintermediate A-1 with 3-fluoro-2-methoxybenzoic acid. MS (ESI) masscalcd. for C₁₉H₁₉F₂N₃O₂, 359.1; m/z found 360.2 [M+H]⁺. MP=134.7° C. ¹HNMR (DMSO-D₆): 8.00 (d, J=2.9 Hz, 0.5H), 7.80 (d, J=2.9 Hz, 0.5H),7.45-7.26 (m, 2H), 7.24-7.06 (m, 2H), 6.96 (d, J=6.0 Hz, 0.5H), 6.89 (d,J=5.8 Hz, 0.5H), 6.56 (dd, J=9.1, 3.6 Hz, 0.5H), 6.48 (dd, J=9.2, 3.6Hz, 0.5H), 4.83 (t, J=4.3 Hz, 0.5H), 4.56 (t, J=4.7 Hz, 0.5H), 4.18-3.98(m, 1H), 3.95-3.81 (m, 3.5H), 3.64 (t, J=4.6 Hz, 0.5H), 2.35-2.14 (m,1H), 1.96-1.43 (m, 4H), 1.30-1.13 (m, 1H).

Example 238(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A:(1S,2R,4R)—N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-aminehydrochloride. To the intermediate of Example 181 Step A (100 mg, 0.3mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.8 mL). The reactionwas allowed to proceed overnight then concentrated neutralized with 5%Na₂CO₃ (aq) and extracted with DCM (2×). The combined organics weredried (Na₂SO₄) to give the title compound of step A that was usedwithout further purification.

Step B:(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.To the title compound of step A (1.44 g, 5.6 mmol) in DCM (56 mL) wasadded DIPEA (1.25 mL, 7.3 mmol) and intermediate A-2 (1.43 g, 6.1 mmol).Then T3P (50% solution in DMF, 10 mL, 17 mmol) was added dropwise andthe reaction heated at 45° C. for 16 h. After allowing to cool to rt,DCM was added and the mixture washed with H₂O then saturated NaHCO₃(aq). The combined aq layers were extracted with DCM. The combinedorganic layers were dried (Na₂SO₄). Purification via silica gelchromatography (10-100% EtOAc in hexanes) gave the title compound (2 g,78%). MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.2; m/z found 459.1[M+H]⁺. ¹H NMR (CDCl₃) 8.91-8.73 (m, 2H), 8.35-8.22 (m, 1H), 8.19 (s,1H), 7.66 (s, 1H), 7.44-7.13 (m, 4H), 4.79-4.68 (m, 1H), 4.46-4.35 (m,1H), 4.12-4.03 (m, 1H), 2.22-2.00 (m, 2H), 1.99-1.84 (m, 1H), 1.79-1.45(m, 3H).

Example 239(2-ethoxynaphthalen-1-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with2-ethoxy-1-naphthoic acid. MS (ESI) mass calcd. for C₂₄H₂₃F₃N₄O₂, 456.2;m/z found 457.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.31 (m, 0.3H), 8.18 (s,0.5H), 8.08-7.98 (m, 0.3H), 7.96-7.67 (m, 3.6H), 7.57-7.32 (m, 2H),7.31-7.16 (m, 1.3H), 7.10-7.04 (m, 0.2H), 6.34 (d, J=9.1 Hz, 0.5H),5.90-5.75 (m, 0.3H), 5.17-4.95 (m, 1H), 4.70 (d, J=7.1 Hz, 0.2H),4.49-4.07 (m, 2.7H), 3.90 (td, J=7.4, 2.9 Hz, 0.2H), 3.77-3.65 (m,0.3H), 3.62-3.56 (m, 0.2H), 3.39 (d, J=5.1 Hz, 0.4H), 2.30-1.94 (m, 2H),1.81-1.47 (m, 5H), 1.47-1.33 (m, 2H).

Example 240isoquinolin-4-yl((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withisoquinoline-4-carboxylic acid. MS (ESI) mass calcd. for C₂₁H₁₈F₃N₅O,413.2; m/z found 414.2 [M+H]⁺. ¹H NMR (CDCl₃): 9.31 (s, 0.5H), 9.13 (s,0.5H), 8.68-8.49 (m, 1H), 8.40-7.53 (m, 5.5H), 7.42 (s, 0.5H), 6.20 (s,0.5H), 4.99 (s, 1.5H), 4.21 (s, 0.5H), 4.06-3.77 (m, 1.5H), 2.27-1.43(m, 6H).

Example 241(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-5. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/zfound 460.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.31 (s, 0.3H), 8.18 (s, 0.7H), 7.91(s, 1.5H), 7.87-7.77 (m, 1H), 7.54 (s, 0.8H), 7.48-7.39 (m, 0.7H),7.35-7.28 (m, 1.7H), 6.97 (dd, J=8.5, 2.5 Hz, 0.3H), 6.87 (d, J=8.3 Hz,0.7H), 6.29 (s, 0.3H), 4.85-4.79 (m, 0.7H), 4.75-4.70 (m, 0.3H),4.40-4.22 (m, 1H), 4.09-4.03 (m, 0.3H), 3.99 (s, 0.7H), 3.94-3.83 (m,3H), 2.19-1.41 (m, 6H).

Example 242(2-methoxy-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-13. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/zfound 460.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.37-8.30 (m, 0.3H), 8.25-8.17 (m,0.7H), 7.97-7.85 (m, 1.5H), 7.84-7.74 (m, 0.8H), 7.65-7.56 (m, 0.4H),7.55-7.37 (m, 2.7H), 7.05-6.94 (m, 1H), 6.17-5.98 (m, 0.2H), 5.90-5.66(m, 0.4H), 5.02-4.86 (m, 0.7H), 4.86-4.71 (m, 0.3H), 4.45-4.18 (m,0.8H), 4.05 (s, 0.7H), 3.97-3.75 (m, 3.3H), 3.62-3.57 (m, 0.2H),2.25-1.29 (m, 6H).

Example 243(5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-7. MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.2; m/z found459.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.88-8.79 (m, 1.7H), 8.77-8.69 (m, 0.3H),8.36-8.14 (m, 1.8H), 8.01 (dd, J=8.6, 5.4 Hz, 1H), 7.81 (s, 0.2H),7.42-7.30-7.02 (m, 3.8H), 6.26 (d, J=7.8 Hz, 0.2H), 4.90-4.81 (m, 0.8H),4.74 (d, J=5.2 Hz, 0.2H), 4.42 (s, 0.8H), 4.27 (s, 0.2H), 4.12-3.96 (m,1H), 2.29-1.39 (m, 6H).

Example 244(5-(4-fluorophenyl)-2-methylthiazol-4-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) masscalcd. for C₂₂H₁₉F₄N₅OS, 477.2; m/z found 478.1 [M+H]⁺. ¹H NMR (CDCl₃):8.32-8.20 (m, 1H), 7.95-7.84 (m, 1H), 7.56-7.40 (m, 2H), 7.15-7.04 (m,2H), 6.97-6.77 (m, 0.8H), 6.01-5.88 (m, 0.2H), 4.85 (t, J=4.5 Hz, 1H),4.21-3.90 (m, 2H), 2.80-2.56 (m, 3H), 2.19-1.95 (m, 1.7H), 1.93-1.31 (m,4.3H).

Example 245(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-24. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.2; m/zfound 444.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.29-8.23 (m, 0.2H), 8.21-8.15 (m,0.8H), 7.95-7.88 (m, 1.6H), 7.84-7.74 (m, 1.3H), 7.62-7.39 (m, 1.2H),7.37-7.19 (m, 2.7H), 5.81 (s, 0.2H), 4.79-4.65 (m, 0.8H), 4.61-4.51 (m,0.2H), 4.38-3.90 (m, 2H), 2.19 (s, 3H), 2.14-1.42 (m, 6H).

Example 246(3-ethoxyisoquinolin-4-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-22. MS (ESI) mass calcd. for C₂₃H₂₂F₃N₅O₂, 457.2; m/zfound 458.3 [M+H]⁺. ¹H NMR (CDCl₃): 9.01-8.92 (m, 0.8H), 8.82 (s, 0.2H),8.35 (s, 0.5H), 8.22 (s, 0.3H), 8.05 (s, 0.1H), 8.00-7.85 (m, 1.6H),7.84-7.71 (m, 1H), 7.71-7.54 (m, 1.2H), 7.50-7.39 (m, 0.8H), 7.39-7.31(m, 0.4H), 7.18 (s, 0.3H), 6.11 (s, 0.1H), 5.95 (d, J=8.8 Hz, 0.3H),5.83 (d, J=8.0 Hz, 0.4H), 5.15-5.06 (m, 0.3H), 5.06-4.94 (m, 0.7H),4.92-4.72 (m, 0.5H), 4.68-4.41 (m, 1.5H), 4.40-4.30 (m, 0.3H), 4.24-4.07(m, 0.4H), 3.89-3.81 (m, 0.2H), 3.81-3.67 (m, 0.7H), 3.51 (d, J=5.1 Hz,0.3H), 2.30-1.95 (m, 2.5H), 1.91-1.21 (m, 6.5H).

Example 247(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-3. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found445.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.32 (s, 0.4H), 8.18 (s, 0.6H), 7.96 (s,1.3H), 7.88 (d, J=4.6 Hz, 1.1H), 7.79 (d, J=7.7 Hz, 0.5H), 7.73-7.52 (m,1.5H), 7.35-7.27 (m, 0.5H), 7.18 (s, 0.7H), 6.28 (s, 0.4H), 4.89-4.70(m, 1H), 4.42-4.19 (m, 1H), 4.03-3.81 (m, 1H), 2.76-2.56 (m, 3H),2.26-1.40 (m, 6H).

Example 248(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-4. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found445.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.51-8.35 (m, 1.6H), 8.29 (s, 0.7H), 8.17(s, 0.3H), 7.92-7.80 (m, 1H), 7.76-7.60 (m, 1.3H), 7.35-7.18 (m, 1.4H),6.81-6.61 (m, 0.7H), 4.95-4.85 (m, 0.3H), 4.84-4.75 (m, 0.7H), 4.49-4.32(m, 1H), 4.07 (t, J=4.4 Hz, 0.7H), 3.93 (s, 0.3H), 2.70-2.54 (m, 3H),2.22 (dd, J=13.1, 8.0 Hz, 0.4H), 2.14-1.46 (m, 5.6H).

Example 249(4-methoxy-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-15. MS (ESI) mass calcd. for C₂₃H₂₁F₃N₆O₂, 470.2; m/zfound 471.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.89-8.69 (m, 2H), 8.38-8.12 (m,2H), 7.81-7.74 (m, 0.1H), 7.70-7.62 (m, 0.1H), 7.49-7.28 (m, 3.8H), 6.91(dd, J=8.4, 2.6 Hz, 0.9H), 6.48-6.39 (m, 0.1H), 4.85-4.77 (m, 0.9H),4.73-4.67 (m, 0.1H), 4.48-4.34 (m, 0.9H), 4.24 (s, 0.1H), 4.09 (d, J=5.0Hz, 1H), 3.94-3.79 (m, 3H), 2.18 (dd, J=13.0, 8.1 Hz, 1H), 2.13-1.37 (m,5H).

Example 250(1H-benzo[d]imidazol-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with1H-benzo[d]imidazole-2-carboxylic acid. MS (ESI) mass calcd. forC₁₉H₁₇F₃N₆O, 402.1; m/z found 403.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.35-7.61(m, 3.5H), 7.40-7.13 (m, 3.5H), 6.26-5.75 (m, 1H), 5.06-4.63 (m, 1.5H),4.27-3.95 (m, 1.5H), 2.86-2.47 (m, 1H), 2.33-1.45 (m, 5H).

Example 251(1-methyl-1H-benzo[d]imidazol-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with1-methyl-1H-benzo[d]imidazole-2-carboxylic acid. MS (ESI) mass calcd.for C₂₀H₁₉F₃N₆O, 416.2; m/z found 417.2 [M+H]⁺.

Example 252(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-16. MS (ESI) mass calcd. for C₂₀H₁₇F₄N₇O, 447.1; m/zfound 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.30 (s, 0.3H), 8.19 (s, 0.7H),7.96-7.75 (m, 2.8H), 7.58-7.49 (m, 0.3H), 7.45-7.11 (m, 3.7H), 5.83 (s,0.2H), 4.80-4.58 (m, 1H), 4.38-4.25 (m, 0.8H), 4.24-4.13 (m, 0.2H),4.13-4.04 (m, 0.2H), 3.97 (d, J=4.9 Hz, 0.8H), 2.22-2.07 (m, 1H),2.07-1.40 (m, 5H).

Example 253 (4-(difluoromethoxy)-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-23. MS (ESI) mass calcd. for C₂₁H₁₈F₅N₇O₂, 495.1; m/zfound 496.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.32 (s, 0.3H), 8.19 (s, 0.7H),7.98-7.81 (m, 2.4H), 7.77 (d, J=2.3 Hz, 0.4H), 7.61 (d, J=2.4 Hz, 0.7H),7.58-7.45 (m, 1H), 7.39 (d, J=8.4 Hz, 0.7H), 7.21 (dd, J=8.4, 2.4 Hz,0.5H), 7.18-7.00 (m, 0.9H), 6.59 (td, J=72.6, 31.4 Hz, 1H), 6.33-6.16(m, 0.4H), 4.92-4.70 (m, 1H), 4.43-4.19 (m, 1H), 4.09-3.83 (m, 1H),2.30-1.44 (m, 6H).

Example 254(3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-17. MS (ESI) mass calcd. for C₂₁H₁₈F₄N₆O₂, 462.1; m/zfound 463.3 [M+H]. ¹H NMR (CDCl₃): 8.31 (s, 0.3H), 8.18 (s, 0.7H), 8.09(s, 0.3H), 7.75-7.68 (m, 0.7H), 7.63 (td, J=8.0, 5.0 Hz, 0.3H), 7.49(td, J=7.9, 5.1 Hz, 0.7H), 7.44-7.13 (m, 2.6H), 5.79 (d, J=8.0 Hz,0.4H), 4.88-4.67 (m, 1H), 4.40-4.22 (m, 1H), 4.10-3.88 (m, 1H), 2.52 (s,3H), 2.28-1.54 (m, 6H).

Example 255(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-18. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/zfound 460.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.32 (s, 0.3H), 8.19 (s, 0.7H),7.96-7.76 (m, 2.5H), 7.74-7.63 (m, 1H), 7.56 (s, 1H), 7.07 (dd, J=8.9,2.9 Hz, 0.4H), 7.03-6.92 (m, 1H), 6.87 (d, J=2.9 Hz, 0.8H), 6.17-6.05(m, 0.3H), 4.89-4.70 (m, 1H), 4.43-4.19 (m, 1H), 4.10-3.94 (m, 1H),3.92-3.75 (m, 3H), 2.25-1.43 (m, 6H).

Example 256(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-10. MS (ESI) mass calcd. for C₂₀H₁₇F₄N₇O, 447.2; m/zfound 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.32 (s, 0.3H), 8.20 (s, 0.7H),8.02-7.87 (m, 1.5H), 7.88-7.71 (m, 1.5H), 7.54 (s, 0.7H), 7.38-7.00 (m,3H), 6.32-6.08 (m, 0.3H), 4.92-4.68 (m, 1H), 4.46-4.20 (m, 1H),4.12-3.88 (m, 1H), 2.28-1.39 (m, 6H).

Example 257(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-12. MS (ESI) mass calcd. for C₂₀H₁₇F₄N₇O, 447.2; m/zfound 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.33 (s, 0.3H), 8.20 (s, 0.7H),8.01-7.79 (m, 2.4H), 7.73 (dd, J=9.4, 2.6 Hz, 0.4H), 7.63-7.44 (m,1.7H), 7.38 (dd, J=8.5, 5.7 Hz, 0.7H), 7.21-6.94 (m, 1.4H), 6.20 (d,J=8.5 Hz, 0.4H), 4.91-4.73 (m, 1H), 4.46-4.17 (m, 1H), 4.09-3.85 (m,1H), 2.25-1.44 (m, 6H).

Example 258(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 withintermediate A-11. MS (ESI) mass calcd. for C₂₀H₁₇F₄N₇O, 447.2; m/zfound 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.29 (m, 0.3H), 8.20 (s, 0.7H),8.01-7.60 (m, 3H), 7.60-7.11 (m, 3.2H), 7.03-6.89 (m, 0.2H), 6.20-6.06(m, 0.2H), 5.45-5.34 (m, 0.2H), 5.16-5.04 (m, 0.2H), 4.99-4.75 (m, 1H),4.49-4.16 (m, 1H), 4.13-4.00 (m, 0.3H), 3.88 (d, J=5.2 Hz, 0.5H), 3.69(d, J=5.1 Hz, 0.2H), 2.33-1.36 (m, 6H).

Example 259(6-methylimidazo[2,1-b]thiazol-5-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting 2 intermediate A-1 with6-methylimidazo[2,1-b]thiazole-5-carboxylic acid. MS (ESI) mass calcd.for C₁₈H₁₇F₃N₆OS, 422.2; m/z found 423.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.26(s, 1H), 7.91-7.75 (m, 2H), 6.96-6.80 (m, 1H), 5.91 (s, 1H), 4.58 (d,J=5.0 Hz, 1H), 4.42 (t, J=4.8 Hz, 1H), 4.21-4.05 (m, 1H), 2.49 (s, 3H),2.25 (dd, J=13.2, 7.5 Hz, 1H), 2.10-1.88 (m, 2H), 1.73-1.54 (m, 3H).

Example 260(3-fluoro-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A:(3-fluoro-2-iodophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 238 substituting intermediate A-2 with3-fluoro-2-iodobenzoic acid. MS (ESI) mass calcd. for C₁₈H₁₅F₄IN₄O,506.0; m/z found 507.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.27-8.14 (m, 1H),8.10-7.81 (m, 1H), 7.48-7.32 (m, 0.5H), 7.23-6.83 (m, 2.5H), 6.66-5.98(m, 1H), 4.94-4.69 (m, 1H), 4.31-4.14 (m, 0.5H), 4.08-3.90 (m, 0.5H),3.90-3.75 (m, 0.5H), 3.72-3.44 (m, 0.5H), 2.27-1.41 (m, 6H).

Step B:(3-fluoro-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.The title compound of step A (35 mg) and 2-(tributylstannyl)oxazole (17μL) were dissolved in DME (1 mL). The solution was degassed with N₂ asCuI (1 mg) and Pd(PPh₃)₄ (4 mg) was added. The reaction was heated at120° C. for 3 h. Additional CuI and Pd(PPh₃)₄ and the reaction purgedwith N₂. Heating was continued overnight. The reaction was cooled to rt,filtered through a pad of celite and purified via prep HPLC to give thetitle compound (12 mg, 39%). MS (ESI) mass calcd. for C₂₁H₁₇F₄N₅O₂,447.1; m/z found 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.34 (s, 1H), 8.16 (s,1H), 7.98-7.78 (m, 1H), 7.69 (s, 0.8H), 7.60-7.06 (m, 4H), 6.80-6.61 (m,0.2H), 4.92-4.66 (m, 1H), 4.46-4.23 (m, 1H), 4.06-3.80 (m, 1H),2.36-1.51 (m, 6H).

Example 261(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-methoxyphenyl)methanone

Example 262(3-fluoro-2-(pyridazin-3-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 260 substituting2-(tributylstannyl)oxazole with 3-(tributylstannyl)pyridazine. MS (ESI)mass calcd. for C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.1 [M+H]⁺. ¹H NMR (500MHz, Chloroform-d) 9.25-9.14 (m, 1H), 8.50 (s, 0.5H), 8.28 (s, 0.8H),8.17 (s, 0.5H), 7.97-7.80 (m, 1.5H), 7.72-7.59 (m, 1H), 7.55-7.41 (m,1H), 7.34-7.18 (m, 2.2H), 6.96 (d, J=8.1 Hz, 0.5H), 4.79-4.72 (m,0.55H), 4.71-4.64 (m, 0.45H), 4.53-4.43 (m, 0.6H), 4.38-4.28 (m, 0.45H),4.18 (s, 0.4H), 4.13-4.05 (m, 0.55H), 2.30-1.47 (m, 6H).

Example 263(3-methyl-2-(pyridazin-3-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A:(2-iodo-3-methylphenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 238 substituting intermediate A-2 with2-iodo-3-methylbenzoic acid. MS (ESI) mass calcd. for C₁₉H₁₈F₃IN₄O,502.0; m/z found 503.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.26-8.03(m, 1.4H), 7.88-6.60 (m, 4.6H), 4.93-4.58 (m, 1H), 4.32-4.15 (m, 0.4H),3.92 (s, 0.4H), 3.86-3.76 (m, 0.6H), 3.57 (s, 0.6H), 2.51 (s, 1.4H),2.40 (s, 1.6H), 2.21-0.66 (m, 6H).

Step B:(3-methyl-2-(pyridazin-3-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 260 Step B substituting2-(tributylstannyl)oxazole with 3-(tributylstannyl)pyridazine. MS (ESI)mass calcd. for C₂₃H₂₁F₃N₆O, 454.2; m/z found 455.2 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) 9.22 (dd, J=4.9, 1.7 Hz, 0.25H), 9.19 (dd, J=4.8, 1.8Hz, 0.75H), 8.57 (s, 0.75H), 8.27 (s, 0.25H), 8.21 (s, 0.25H), 8.16 (s,0.75H), 7.97 (s, 0.75H), 7.72-7.56 (m, 2H), 7.44-7.27 (m, 2.25H),7.25-7.19 (m, 0.75H), 6.40 (d, J=8.0 Hz, 0.25H), 4.68-4.62 (m, 0.75H),4.59-4.54 (m, 0.25H), 4.39 (ddd, J=9.3, 8.1, 3.9 Hz, 0.75H), 4.28-4.15(m, 0.5H), 4.08-4.03 (m, 0.75H), 2.32 (s, 0.75H), 2.21 (s, 2.25H),2.18-1.42 (m, 6H).

Example 264(3-fluoro-2-(pyridazin-4-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 260 substituting2-(tributylstannyl)oxazole with 4-(tributylstannyl)pyridazine. MS (ESI)mass calcd. for C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.2 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) 9.38-9.20 (m, 2H), 8.28 (s, 0.6H), 8.19 (s, 0.4H),8.00 (s, 0.6H), 7.94 (s, 0.4H), 7.71-7.63 (m, 0.6H), 7.62-7.50 (m, 1H),7.40-7.29 (m, 1H), 7.24-7.08 (m, 1.4H), 5.24 (s, 0.4H), 4.80 (s, 0.6H),4.67 (s, 0.4H), 4.61 (d, J=5.3 Hz, 0.6H), 4.02-3.92 (m, 0.6H), 3.85-3.75(m, 0.4H), 3.70-3.59 (m, 1H), 1.90-2.07 (m, 1H), 1.84-0.79 (m, 5H).

Example 265(3-fluoro-2-(pyrazin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 260 substituting2-(tributylstannyl)oxazole with 2-(tributylstannyl)pyrazine. MS (ESI)mass calcd. for C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.2 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) 8.99-8.94 (m, 1H), 8.69 (d, J=2.6 Hz, 1H), 8.58-8.51(m, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 7.44-7.37 (m, 1H),7.25-7.20 (m, 2H), 4.80-4.74 (m, 1H), 4.40 (td, J=8.6, 3.6 Hz, 1H), 4.05(d, J=5.1 Hz, 1H), 2.24-2.16 (m, 1H), 1.78-1.67 (m, 2H), 1.62-1.51 (m,2H), 1.41-1.29 (m, 1H).

Example 266(3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 263 substituting3-(tributylstannyl)pyridazine with 2-(tributylstannyl)oxazole. MS (ESI)mass calcd. for C₂₂H₂₀F₃N₅O₂, 443.2; m/z found 444.2 [M+H]⁺. ¹H NMR (500MHz, Chloroform-d) 8.57 (s, 1H), 8.14 (s, 1H), 7.88 (d, J=0.9 Hz, 1H),7.79 (d, J=1.4 Hz, 1H), 7.33-7.23 (m, 3H), 7.20-7.14 (m, 1H), 4.82-4.75(m, 1H), 4.29 (td, J=8.5, 3.7 Hz, 1H), 3.94 (d, J=4.9 Hz, 1H), 2.28 (s,3H), 2.16-1.45 (m, 6H).

Example 267(4-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 withintermediate A-25. MS (ESI) mass calcd. for: C₂₂H₁₈F₄N₆O, 458.1; m/zfound 459.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.89-8.81 (m, 1.7H),8.80-8.73 (m, 0.3H), 8.33-7.87 (m, 2H), 7.80 (s, 0.2H), 7.74-7.66 (m,0.8H), 7.56-7.31 (m, 2.8H), 7.21-7.14 (m, 0.2H), 7.14-7.06 (m, 0.8H),6.58 (s, 0.2H), 4.88-4.78 (m, 0.8H), 4.72 (d, J=5.2 Hz, 0.2H), 4.40 (s,0.8H), 4.26 (s, 0.2H), 4.10-3.97 (m, 1H), 2.27-1.39 (m, 6H).

Example 268(3-fluoro-2-(pyridin-4-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 260 substituting2-(tributylstannyl)oxazole with 4-(tributylstannyl)pyridine. MS (ESI)mass calcd. for: C₂₃H₁₉F₄N₅O, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (500MHz, Chloroform-d) 8.78-8.61 (m, 2H), 8.28 (s, 0.6H), 8.15 (s, 0.4H),7.87 (s, 1H), 7.72-7.28 (m, 4.2H), 7.23-7.02 (m, 1.4H), 5.49 (s, 0.4H),4.67-4.60 (m, 0.4H), 4.56 (d, J=5.3 Hz, 0.6H), 3.99-3.89 (m, 0.6H),3.82-3.72 (m, 0.4H), 3.65-3.58 (m, 0.6H), 3.56 (d, J=5.4 Hz, 0.4H),2.00-0.80 (m, 6H).

Example 269(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.To intermediate B-5 (250 mg, 1.2 mmol) and K₂CO₃ (244 mg, 1.8 mmol) inDMF (1.7 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (258 mg,1.4 mmol). After heating at 70° C. for 17 h, the mixture was cooled tort, diluted with EtOAc and H₂O. The aqueous layer was extracted withEtOAc (3×). The combined organics were washed with 4% MgSO₄ (aq) anddried (MgSO₄). Purification via silica gel chromatography (0-30% EtOAcin hexanes) gave the title compound (356 mg, 84%). MS (ESI) mass calcd.for C₁₆H₂₁F₃N₄O₂, 358.2; m/z found 359.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) 8.58-8.37 (m, 2H), 5.70 (s, 1H), 4.30 (s, 1H), 1.78-1.68(m, 1H), 4.25-4.17 (m, 1H), 1.89-1.79 (m, 1H), 4.12-4.03 (m, 1H), 2.03(dd, J=13.1, 7.8 Hz, 1H), 1.63-1.37 (m, 12H).

Step B:(1S,2R,4R)—N-(5-(trifluoromethyl)pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine.To the title compound of step A (355 mg, 1 mmol) in DCM (9.7 mL) wasadded 4M HCl in dioxane (1.2 mL). The reaction was allowed to proceedovernight then concentrated and neutralized with 5% Na₂CO₃ (aq) andextracted with DCM (2×). The combined organics were dried (Na₂SO₄) togive the title compound of step B that was used without furtherpurification.

Step C:(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.To the title compound of step B (25 mg, 0.1 mmol) in DCM (1 mL) wasadded DIPEA (22 μL, 0.13 mmol) and intermediate A-16 (22 mg, 0.1 mmol).Then T3P (50% solution in DMF, 0.17 mL, 0.29 mmol) was added dropwiseand the reaction heated at 45° C. for 12 h. After allowing to cool tort, DCM was added and the mixture washed with H₂O then saturated NaHCO₃(aq). The combined aq layers were extracted with DCM. The combinedorganic layers were dried (Na₂SO₄). Purification was performed usingAgilent prep method X to give the title compound (35 mg, 80%). MS (ESI)mass calcd. for: C₂₀H₁₇F₄N₇O, 447.1; m/z found 448.2 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) 8.50 (s, 0.9H), 8.41 (s, 1.1H), 8.09 (s, 0.9H), 7.95(s, 1.1H), 7.56-7.47 (m, 0.5H), 7.44-7.32 (m, 1H), 7.33-7.23 (m, 1.5H),7.20-7.14 (m, 0.5H), 6.18 (d, J=8.6 Hz, 0.5H), 4.83-4.74 (m, 0.5H), 4.67(d, J=5.2 Hz, 0.5H), 4.34-4.19 (m, 1H), 4.11-4.04 (m, 0.5H), 3.99 (d,J=4.8 Hz, 0.5H), 2.21-1.44 (m, 6H).

Example 270((1S,2R,4R)-2-((3-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Step A: (1S,2R,4R)-tert-butyl2-((3-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to Example 269 step A substituting2-chloro-5-(trifluoromethyl)pyrimidine with3-bromo-8-chloroimidazo[1,2-a]pyrazine. MS (ESI) mass calcd. for:C₁₇H₂₂BrN₅O₂, 407.1; m/z found 408.1 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) 7.45 (s, 1H), 7.43 (d, J=4.7 Hz, 1H), 7.40 (d, J=4.7 Hz,1H), 6.15 (s, 1H), 4.37-4.27 (m, 2H), 4.27-4.21 (m, 1H), 2.08 (dd,J=13.0, 7.8 Hz, 1H), 1.90-1.33 (m, 14H).

Step B:N-((1S,2R,4R)-7-azabicyclo[2.2.1]heptan-2-yl)-3-bromoimidazo[1,2-a]pyrazin-8-amine.Prepared analogous to Example 269 step B using title compound of step A.

Step C:((1S,2R,4R)-2-((3-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone.Prepared analogous to Example 269 step C substituting intermediate A-16with intermediate A-2. MS (ESI) mass calcd. for: C₂₃H₁₉BrFN₇O, 507.1;m/z found 508.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.92 (d, J=4.9Hz, 0.7H), 8.88 (d, J=4.9 Hz, 1.3H), 7.53-7.03 (m, 7.6H), 5.82 (d, J=7.6Hz, 0.4H), 4.81-4.75 (m, 0.6H), 4.71 (d, J=5.1 Hz, 0.4H), 4.47-4.37 (m,0.6H), 4.31-4.22 (m, 0.4H), 4.13-4.07 (m, 0.6H), 4.06-3.99 (m, 0.4H),2.26-1.36 (m, 6H).

Example 271(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 withintermediate A-2. MS (ESI) mass calcd. for: C₂₂H₁₈F₄N₆O, 458.1; m/zfound 459.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.90 (d, J=5.0 Hz,2H), 8.49 (s, 1H), 8.44-8.31 (m, 2H), 7.43-7.32 (m, 2H), 7.26-7.14 (m,2H), 4.80-4.75 (m, 1H), 4.45-4.37 (m, 1H), 4.09 (d, J=5.0 Hz, 1H), 2.22(dd, J=12.9, 8.0 Hz, 1H), 2.11-1.51 (m, 5H).

Example 272(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 withintermediate A-24. MS (ESI) mass calcd. for: C₂₁H₂₀F₃N₇O, 443.2; m/zfound 444.2 [M+H]. ¹H NMR (400 MHz, Chloroform-d) 8.49 (s, 0.8H), 8.41(s, 1.2H), 8.02 (s, 0.8H), 7.91 (s, 1.2H), 7.47-7.39 (m, 1H), 7.38-7.28(m, 2H), 7.23-7.16 (m, 0.6H), 5.98 (d, J=8.4 Hz, 0.4H), 4.77-4.68 (m,0.6H), 4.60 (d, J=5.1 Hz, 0.4H), 4.29-4.17 (m, 1H), 4.11-4.03 (m, 0.4H),3.99 (d, J=5.0 Hz, 0.6H), 2.27 (s, 1.3H), 2.24 (s, 1.7H), 2.18-1.41 (m,6H).

Example 273(3-methyl-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 withintermediate A-26. MS (ESI) mass calcd. for: C₂₃H₂₁F₃N₆O, 454.2; m/zfound 455.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.85 (d, J=5.0 Hz,2H), 8.50 (d, J=9.2 Hz, 1H), 8.17 (s, 1H), 7.66 (d, J=1.3 Hz, 1H), 7.37(t, J=5.0 Hz, 1H), 7.31-7.18 (m, 3H), 4.73-4.67 (m, 1H), 4.35 (td,J=8.7, 3.7 Hz, 1H), 4.14-4.09 (m, 1H), 2.29 (s, 3H), 2.19-1.45 (m, 6H).

Example 274(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl2-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to Example 269 step A substituting2-chloro-5-(trifluoromethyl)pyrimidine with8-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine. MS (ESI)mass calcd. for: C₁₇H₂₁F₃N₆O₂, 398.2; m/z found 399.2 [M+H]⁺. ¹H NMR(500 MHz, Chloroform-d) 7.51-7.48 (m, 1H), 7.48-7.45 (m, 1H), 6.58 (d,J=7.6 Hz, 1H), 4.41-4.25 (m, 3H), 1.94-1.83 (m, 1H), 2.12 (dd, J=13.1,7.8 Hz, 1H), 1.83-1.70 (m, 2H), 1.59-1.52 (m, 1H), 1.50-1.41 (m, 10H).

Step B:N-((1S,2R,4R)-7-azabicyclo[2.2.1]heptan-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-amine.Prepared analogous to Example 269 step B using title compound of step A.

Step C:(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 269 step C substituting intermediate A-16with intermediate A-2. MS (ESI) mass calcd. for: C₂₃H₁₈F₄N₈O, 498.2; m/zfound 499.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.99 (d, J=4.9 Hz,0.6H), 8.95 (d, J=5.0 Hz, 1.4H), 8.72 (s, 0.7H), 7.55-7.28 (m, 4.6H),7.21-7.10 (m, 1.4H), 6.18 (d, J=7.5 Hz, 0.3H), 4.88-4.80 (m, 0.7H), 4.75(d, J=5.1 Hz, 0.3H), 4.67 (s, 0.7H), 4.33 (s, 0.3H), 4.16-4.06 (m, 1H),2.27 (dd, J=12.7, 8.2 Hz, 0.7H), 2.11 (dd, J=13.0, 8.1 Hz, 0.3H),2.04-1.41 (m, 5H).

Example 275 methyl5-(((1S,2R,4R)-7-(3-fluoro-2-(pyrimidin-2-yl)benzoyl)-7-azabicyclo[2.2.1]heptan-2-yl)amino)pyrazine-2-carboxylate

Step A: (1S,2R,4R)-tert-butyl2-((5-(methoxycarbonyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to Example 269 step A substituting2-chloro-5-(trifluoromethyl)pyrimidine with methyl5-chloropyrazine-2-carboxylate. MS (ESI) mass calcd. for: C₁₇H₂₄N₄O₄,348.2; m/z found 349.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.77 (d,J=1.4 Hz, 1H), 7.88 (d, J=1.4 Hz, 1H), 5.55 (s, 1H), 4.34-4.27 (m, 1H),4.25-4.18 (m, 1H), 4.12-4.06 (m, 1H), 3.95 (s, 3H), 2.12-2.05 (m, 1H),1.92-1.72 (m, 2H), 1.63-1.38 (m, 12H).

Step B: methyl5-((1S,2R,4R)-7-azabicyclo[2.2.1]heptan-2-ylamino)pyrazine-2-carboxylate.Prepared analogous to Example 269 step B using title compound of step A.

Step C: methyl5-(((1S,2R,4R)-7-(3-fluoro-2-(pyrimidin-2-yl)benzoyl)-7-azabicyclo[2.2.1]heptan-2-yl)amino)pyrazine-2-carboxylate.Prepared analogous to Example 269 step C substituting intermediate A-16with intermediate A-2. MS (ESI) mass calcd. for: C₂₃H₂₁FN₆O₃, 448.2; m/zfound 449.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.87 (d, J=4.9 Hz,2H), 8.65 (s, 1H), 8.37 (d, J=9.4 Hz, 1H), 7.67 (s, 1H), 7.42-7.34 (m,2H), 7.24-7.17 (m, 2H), 4.77-4.70 (m, 1H), 4.48-4.39 (m, 1H), 4.07 (d,J=5.1 Hz, 1H), 3.90 (s, 3H), 2.18 (dd, J=13.0, 8.1 Hz, 1H), 2.11-2.00(m, 1H), 1.97-1.62 (m, 3H), 1.58-1.48 (m, 1H).

Example 276(2-iodo-3-methylphenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 with2-iodo-3-methylbenzoic acid. MS (ESI) mass calcd. for: C₁₉H₁₈F₃IN₄O,502.0; m/z found 503.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.59-8.30(m, 2H), 7.32-7.22 (m, 1.4H), 7.19-6.96 (m, 1H), 6.93-6.83 (m, 0.6H),6.02 (s, 0.5H), 5.54 (s, 0.5H), 5.01-4.91 (m, 0.5H), 4.84 (d, J=5.1 Hz,0.5H), 4.28 (s, 0.5H), 4.02 (s, 0.5H), 3.84-3.66 (m, 1H), 2.50 (s,1.5H), 2.43 (s, 1.5H), 2.24-1.39 (m, 6H).

Example 277(3-fluoro-2-iodophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 with3-fluoro-2-iodobenzoic acid. MS (ESI) mass calcd. for: C₁₈H₁₅F₄IN₄O,506.0; m/z found 507.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.57-8.33(m, 2H), 7.42-7.32 (m, 0.5H), 7.16-7.02 (m, 1.5H), 6.99-6.88 (m, 1H),5.99 (d, J=7.6 Hz, 0.5H), 5.55 (s, 0.5H), 5.00-4.91 (m, 0.5H), 4.85 (d,J=5.3 Hz, 0.5H), 4.32-4.24 (m, 0.5H), 4.05-3.97 (m, 0.5H), 3.81-3.71 (m,1H), 2.22-1.93 (m, 2H), 1.91-1.43 (m, 4H).

Example 278(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-methylpyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl2-((5-methylpyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.Prepared analogous to Example 279 step A substituting2-chloro-5-(trifluoromethyl)pyridine with 2-chloro-5-methylpyrazine. MS(ESI) mass calcd. for: C₁₆H₂₄N₄O₂, 304.2; m/z found 305.2 [M+H]⁺. ¹H NMR(400 MHz, Chloroform-d) 7.86 (s, 1H), 7.78 (d, J=1.5 Hz, 1H), 4.71 (s,1H), 4.28 (s, 1H), 4.19 (d, J=4.9 Hz, 1H), 3.95-3.85 (m, 1H), 2.38 (s,3H), 2.11-1.96 (m, 1H), 1.89-1.66 (m, 2H), 1.58-1.33 (m, 12H).

Step B:(1S,2R,4R)—N-(5-methylpyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine.Prepared analogous to Example 279 step B using title compound of step A.

Step C:(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-methylpyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.Prepared analogous to Example 279 step C. MS (ESI) mass calcd. for:C₂₂H₂₁FN₆O, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) 8.87 (d, J=5.0 Hz, 2H), 7.74 (s, 1H), 7.60 (s, 1H),7.41-7.30 (m, 3H), 7.23-7.12 (m, 2H), 4.76-4.68 (m, 1H), 4.30-4.17 (m,1H), 4.08-4.01 (m, 1H), 2.30 (s, 3H), 2.15 (dd, J=12.9, 8.1 Hz, 1H),2.07-1.95 (m, 1H), 1.95-1.84 (m, 1H), 1.74-1.46 (m, 3H).

Example 279(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.In a microwave vial, toluene (8.3 mL) was degassed with N₂ for 10minutes then Pd(OAc)₂ (22 mg, 0.03 mmol) and racemic BINAP (21 mg, 0.03mmol) were added and the solution was degassed with N₂ for 5 minutes.Then intermediate B-5, 2-chloro-5-(trifluoromethyl)pyridine (150 mg,0.83 mmol) and sodium tert-butoxide (115 mg, 1.16 mmol) were added andthe reaction mixture was stirred at 70° C. After 15 h the reactionmixture was filtered through a pad of celite and solvent was evaporated.Purification via silica gel chromatography (0-40% EtOAc in hexanes) gavethe title compound of step A (192 mg, 65%). MS (ESI) mass calcd. for:C₁₇H₂₂F₃N₃O₂, 357.2; m/z found 358.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) 8.33 (s, 1H), 7.61-7.49 (m, 1H), 6.35 (d, J=8.8 Hz, 1H),5.06 (s, 1H), 4.29 (s, 1H), 4.20 (s, 1H), 4.03-3.91 (m, 1H), 2.04 (dd,J=13.0, 7.6 Hz, 1H), 1.89-1.79 (m, 1H), 1.79-1.71 (m, 1H), 1.59-1.37 (m,12H).

Step B:(1S,2R,4R)—N-(5-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine.To the title compound of step A (319 mg, 0.89 mmol) in DCM (8.7 mL) wasadded 4M HCl in dioxane (1.1 mL). The reaction was allowed to proceedovernight then concentrated and neutralized with 5% Na₂CO₃ (aq) andextracted with DCM (2×). The combined organics were dried (Na₂SO₄) togive the title compound of step B that was used without furtherpurification.

Step C:(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.To the title compound of step B (100 mg, 0.39 mmol) in DCM (3.9 mL) wasadded DIPEA (87 μL, 0.51 mmol) and intermediate A-2 (100 mg, 0.43 mmol).Then T3P (50% solution in DMF, 0.7 mL, 1.16 mmol) was added dropwise andthe reaction heated at 45° C. for 12 h. After allowing to cool to rt,DCM was added and the mixture washed with H₂O then saturated NaHCO₃(aq). The combined aq layers were extracted with DCM. The combinedorganic layers were dried (Na₂SO₄). Purification was performed usingAgilent prep method X to give the title compound (61 mg, 34%). MS (ESI)mass calcd. for: C₂₃H₁₉F₄N₅O, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) 8.88 (d, J=4.9 Hz, 2H), 8.22 (s, 1H), 7.67 (d, J=9.3Hz, 1H), 7.43-7.28 (m, 3H), 7.24-7.12 (m, 2H), 6.19 (d, J=8.8 Hz, 1H),4.76-4.68 (m, 1H), 4.43-4.32 (m, 1H), 4.08 (d, J=5.0 Hz, 1H), 2.16 (dd,J=12.9, 8.1 Hz, 1H), 2.08-1.83 (m, 2H), 1.77-1.38 (m, 3H).

Example 280(4-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 279 substituting intermediate A-2 withintermediate A-25. MS (ESI) mass calcd. for: C₂₃H₁₉F₄N₅O, 457.2; m/zfound 458.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.89-8.76 (m, 2H),8.36 (s, 0.2H), 8.26-8.19 (m, 0.8H), 8.05-7.91 (m, 0.4H), 7.70 (dd,J=9.3, 2.7 Hz, 0.6H), 7.60-7.53 (m, 0.3H), 7.48-7.40 (m, 0.3H),7.40-7.28 (m, 2.6H), 7.25-6.99 (m, 1.6H), 6.36 (d, J=8.7 Hz, 0.2H), 5.96(d, J=8.8 Hz, 0.8H), 5.70 (s, 0.2H), 4.87-4.80 (m, 0.8H), 4.73 (d, J=5.3Hz, 0.2H), 4.38 (s, 0.8H), 4.17 (s, 0.2H), 4.06-4.00 (m, 0.8H),4.00-3.94 (m, 0.2H), 2.21 (dd, J=12.9, 8.0 Hz, 0.8H), 2.12-1.35 (m,5.2H).

Example 281(3-methyl-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 withintermediate A-26. MS (ESI) mass calcd. for: C₂₃H₂₁F₃N₆O, 454.2; m/zfound 455.3 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.89-8.85 (m, 2H),8.70 (s, 1H), 8.44-8.32 (m, 2H), 7.34-7.23 (m, 3H), 7.21-7.15 (m, 1H),4.77-4.68 (m, 1H), 4.43-4.33 (m, 1H), 4.11 (d, J=5.1 Hz, 1H), 2.36 (s,3H), 2.19 (dd, J=12.8, 7.9 Hz, 1H), 2.09-1.99 (m, 1H), 1.94-1.85 (m,1H), 1.72-1.48 (m, 3H).

Example 282(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

The title compound of Example 238 (63 mg, 0.14 mmol) was dissolved inDMF (1.4 mL) and then sodium tert-butoxide (15 mg, 0.15 mmol) followedby iodomethane (9 μL, 0.14 mmol) were added. After 15 h at roomtemperature the reaction mixture was diluted with EtOAc and water wasadded. The aqueous phase was extracted twice with EtOAc and the combinedorganic phases were dried over MgSO₄, filtered and evaporated.Purification was performed using Agilent prep method X to give the titlecompound (40 mg, 62%). MS (ESI) mass calcd. for: C₂₃H₂₀F₄N₆O, 472.2; m/zfound 473.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.81 (d, J=4.9 Hz,2H), 8.35 (s, 1H), 8.02 (s, 1H), 7.55-7.46 (m, 1H), 7.34-7.20 (m, 3H),4.81-4.73 (m, 1H), 4.67 (d, J=4.3 Hz, 1H), 4.17-4.08 (m, 1H), 3.05 (s,3H), 2.12 (dd, J=12.8, 8.3 Hz, 1H), 1.98-1.44 (m, 5H).

Example 283(3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 withintermediate A-31. MS (ESI) mass calcd. for: C₂₂H₂₀F₃N₅O₂, 443.2; m/zfound 444.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.48 (s, 1H), 8.35(s, 1H), 7.88-7.78 (m, 1H), 7.68 (s, 0.4H), 7.44-7.21 (m, 3.6H), 7.15(dd, J=6.6, 2.2 Hz, 0.6H), 7.06-6.97 (m, 0.4H), 4.84-4.78 (m, 0.6H),4.73-4.67 (m, 0.4H), 4.33 (td, J=8.4, 3.0 Hz, 0.4H), 4.24 (td, J=8.2,3.7 Hz, 0.6H), 4.04-3.98 (m, 0.4H), 3.97-3.89 (m, 0.6H), 2.47 (s, 1.7H),2.37 (s, 1.3H), 2.19-1.41 (m, 6H).

Example 284(3-fluoro-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

In a microwave vial was dissolved the title compound of Example 277 (30mg, 0.06 mmol) and 2-(tributylstannyl)oxazole (15 μL, 0.07 mmol) in DME(1 mL). The solution was degassed with N₂ for 5 minutes then CuI (1 mg,0.0045 mmol) and Pd(PPh₃)₄ (5 mg, 0.0045 mmol) were added. The reactionwas purged with N₂ and heated at 145° C. for 3 h. The reaction wascooled to rt, filtered through a pad of celite and purified via prepHPLC to give the title compound (19 mg, 72%). MS (ESI) mass calcd. for:C₂₁H₁₇F₄N₅O₂, 447.1; m/z found 448.1 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) 8.49 (s, 1H), 8.36 (s, 0.8H), 7.85 (s, 0.8H), 7.76 (s,0.4H), 7.62-7.45 (m, 1H), 7.43-7.33 (m, 1H), 7.32-7.23 (m, 2H),7.23-7.09 (m, 1H), 4.91-4.85 (m, 0.4H), 4.78 (d, J=5.4 Hz, 0.6H), 4.42(td, J=8.6, 2.8 Hz, 0.6H), 4.28 (td, J=8.2, 3.6 Hz, 0.4H), 4.00-3.95 (m,0.6H), 3.89 (d, J=4.4 Hz, 0.4H), 2.23-1.44 (m, 6H).

Example 285(±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptane-7-carboxylate:To (±)-tert-butyl 2-hydroxy-7-azabicyclo[2.2.1]heptane-7-carboxylate(exo) (52 mg, 0.25 mol) in DMF (5 mL) was added 60 wt % NaH (20 mg, 0.5mmol) in one portion. The reaction was heated at 80° C. for 5 min, then2-chloro-5-(trifluoromethyl)pyrimidine (89.7 mg, 0.49 mmol) was added.After heating at 80° C. for 2 hours, water was added and the mixtureextracted with DCM (3×). The combined organics were dried (Na₂SO₄) andconcentrated. Purification via silica gel chromatography (0-50% EtOAc inhexanes) gave the title compound (20 mg, 23%). MS (ESI) mass calcd. for:C₁₆H₂₀F₃N₃O₃, 359.4; m/z found 260.1 [M-Boc]⁺.

Step B:(±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone:To (±)-tert-butyl2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptane-7-carboxylate(20 mg, 0.06 mmol0 in DCM (2 mL) was added 2 mL (2M HCl in Et₂O) andstirred at rt for 3 h. The reaction mixture was concentrated and placedunder high vacuum for 1 h. To the intermediate in DCM (2 mL) was addedcarboxylic acid (A-2) (13.3 mg, 0.06 mmol), HOBt (13.7 mg, 0.101 mmol),EDCI (19.4 mg, 0.101 mmol) and DIEPA (26 μL, 0.15 mmol). After stirringat rt for 2 h, saturated NaHCO₃ (aq.) was added and the mixture wasextracted with DCM (3×). The combined organics were dried (Na₂SO₄), andconcentrated. Purification via silica gel chromatography (0-100% EtOAcin hexanes) gave the title compound (9 mg, 38%). MS (ESI) mass calcd.for: C₂₂H₁₇F₄N₅O₂, 459.1; m/z found 460.1 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) 8.88 (d, J=4.9 Hz, 1H), 8.81 (d, J=4.9 Hz, 1H), 8.74 (d,J=12.6 Hz, 2H), 7.63-7.27 (m, 3H), 7.14 (t, J=8.9 Hz, 1H), 4.99 (dt,J=8.3, 4.8 Hz, 1H), 4.87-4.66 (m, 1H), 4.16-3.97 (m, 1H), 2.07 (d, J=4.3Hz, 1H), 1.91 (d, J=32.9 Hz, 1H), 1.85-1.68 (m, 2H), 1.66-1.60 (m, 1H),1.51 (dd, J=7.9, 4.8 Hz, 1H).

Example 286(±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptane-7-carboxylate:To (±)-tert-butyl 2-hydroxy-7-azabicyclo[2.2.1]heptane-7-carboxylate(endo) (150 mg, 0.703 mol) in DMF (8 mL) was added 60 wt % NaH (56.3 mg,1.41 mmol) in one portion. The reaction was heated at 80° C. for 5 min,then 2-chloro-5-(trifluoromethyl)pyrimidine (257 mg, 1.4 mmol) wasadded. After heating at 80° C. for 2 hours, water was added and themixture extracted with DCM (3×). The combined organics were dried(Na₂SO₄) and concentrated. Purification via silica gel chromatography(0-50% EtOAc in hexanes) gave the title compound (130 mg, 51%). MS (ESI)mass calcd. for: C₁₆H₂₀F₃N₃O₃, 359.4; m/z found 260.1 [M-Boc]⁺. ¹H NMR(400 MHz, Chloroform-d) 8.82-8.71 (m, 2H), 5.28 (d, J=10.0 Hz, 1H), 4.59(s, 1H), 4.25 (s, 1H), 2.43 (dddd, J=13.1, 10.1, 5.2, 2.8 Hz, 1H),2.18-2.04 (m, 1H), 1.85 (dd, J=7.8, 3.8 Hz, 1H), 1.69 (s, 1H), 1.59 (s,2H), 1.47 (s, 9H).

Step B:(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1R,2S,4S)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone:To (±)-tert-butyl2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptane-7-carboxylate(143 mg, 0.398 mmol) in DCM (3 mL) was added 2M HCl in Et₂O (3 mL).After 3 h at rt the reaction mixture was concentrated and placed underhigh vacuum for 1 h. To the intermediate in DCM (3 mL) was addedcarboxylic acid (A-2) (95.5 mg, 0.438 mmol), HOBt (88.9 mg, 0.658 mmol0,EDCI (126.1 mg, 0.658 mmol) and DIEPA (170 μL, 0.987 mmol). Afterstirring at rt for 2 h, saturated NaHCO₃ (aq.) was added and the mixturewas extracted with DCM (3×). The combined organics were dried (Na₂SO₄),and concentrated. Purification via silica gel chromatography (0-100%EtOAc in hexanes) gave the title compound (78.6 mg, 47%). MS (ESI) masscalcd. for: C₂₂H₁₇F₄N₅O₂, 459.1; m/z found 460.1 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 8.85 (t, J=5.2 Hz, 2H), 8.76 (d, J=12.3 Hz, 2H),7.47 (dd, J=8.5, 5.4 Hz, 1H), 7.29 (td, J=5.4, 4.9, 4.3 Hz, 3H),5.58-5.40 (m, 1H), 5.30 (s, 1H), 5.09-4.92 (m, 1H), 4.67 (s, 1H), 4.34(s, 1H), 4.02 (s, 1H), 2.61-2.39 (m, 1H), 2.32-2.08 (m, 1H), 1.90 (d,J=13.7 Hz, 1H).

Example 287(3-ethoxy-6-methylpyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 withintermediate A-8. MS (ESI) mass calcd. for: C₂₀H₂₂F₃N₅O₂, 421.2; m/zfound 422.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.31 (s, 0.2H), 8.24(s, 0.8H), 8.01-7.81 (m, 1.8H), 7.25-7.09 (m, 2H), 6.15 (d, J=8.0 Hz,0.2H), 5.01-4.93 (m, 0.8H), 4.87-4.80 (m, 0.2H), 4.32-4.24 (m, 0.2H),4.18-4.02 (m, 2.8H), 3.95 (d, J=4.6 Hz, 0.8H), 3.88-3.82 (m, 0.2H),2.55-2.46 (m, 3H), 2.26-1.23 (m, 9H).

Example 288(3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 withintermediate A-27. MS (ESI) mass calcd. for: C₁₉H₁₇F₃N₈O, 430.1; m/zfound 431.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.65 (dd, J=4.7, 1.5Hz, 0.2H), 8.55 (dd, J=4.8, 1.5 Hz, 0.8H), 8.39-8.32 (m, 0.4H),8.29-8.18 (m, 1.6H), 7.97-7.86 (m, 2.2H), 7.70 (s, 0.8H), 7.56 (dd,J=8.3, 4.7 Hz, 0.2H), 7.50 (dd, J=8.3, 4.7 Hz, 0.8H), 7.15 (d, J=8.6 Hz,0.8H), 6.12 (d, J=8.6 Hz, 0.2H), 4.97-4.89 (m, 0.8H), 4.82 (d, J=5.2 Hz,0.2H), 4.29 (td, J=7.9, 2.8 Hz, 1H), 4.12-4.07 (m, 0.2H), 4.04 (d, J=5.0Hz, 0.8H), 2.27-1.43 (m, 6H).

Example 289(2-methoxy-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 withintermediate A-28. MS (ESI) mass calcd. for: C₂₃H₂₁F₃N₆O₂, 470.2; m/zfound 471.2[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.89-8.71 (m, 2H),8.53-8.14 (m, 1.5H), 7.99-7.76 (m, 0.5H), 7.60-7.29 (m, 3.7H), 7.23-6.99(m, 1H), 6.08 (d, J=8.9 Hz, 0.2H), 5.78 (d, J=8.5 Hz, 0.1H), 5.00-4.78(m, 1H), 4.46-4.35 (m, 1H), 4.07 (s, 0.5H), 3.91-3.79 (m, 3.5H),2.32-1.24 (m, 6H).

Example 290(2-fluoro-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 withintermediate A-6. MS (ESI) mass calcd. for: C₂₂H₁₈F₄N₆O, 458.1; m/zfound 459.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.89-8.72 (m, 2H),8.38-8.16 (m, 2H), 7.78 (dd, J=7.8, 1.1 Hz, 1H), 7.55-7.44 (m, 1H),7.43-7.35 (m, 1H), 7.34-7.14 (m, 2H), 4.93-4.85 (m, 1H), 4.50-4.39 (m,1H), 3.98-3.88 (m, 1H), 2.31-1.11 (m, 6H).

Example 291(7-ethoxyquinolin-8-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 withintermediate A-29. MS (ESI) mass calcd. for: C₂₃H₂₂F₃N₅O₂, 457.2 m/zfound 458.2 [M+H]⁺.

Example 292 (2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxyphenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 withintermediate A-30. MS (ESI) mass calcd. for: C₂₄H₂₅F₃N₆O₂, 486.2 m/zfound 487.2 [M+H]⁺.

Example 293(3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 284 substituting title compound of Example277 with title compound of Example 276 and 2-(tributylstannyl)oxazolewith 2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for: C₂₄H₂₂F₃N₅O,453.2 m/z found 454.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.72-8.66(m, 1H), 8.45 (s, 0.5H), 8.39 (s, 1.5H), 7.86-7.75 (m, 1H), 7.52-7.44(m, 1H), 7.38-7.20 (m, 4.2H), 7.18-7.12 (m, 0.8H), 4.72-4.65 (m, 0.8H),4.49-4.45 (m, 0.2H), 4.32 (s, 0.8H), 4.03-3.95 (m, 1H), 3.88-3.83 (m,0.2H), 2.26 (s, 2.2H), 2.23 (s, 0.8H), 2.16 (dd, J=12.8, 7.9 Hz, 0.8H),1.98-1.08 (m, 5.2H).

Example 294(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 279 substituting intermediate A-2 withintermediate A-16. MS (ESI) mass calcd. for: C₂₁H₁₈F₄N₆O, 446.1 m/zfound 447.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.33 (s, 0.2H), 8.23(s, 0.8H), 7.96 (s, 1.55H), 7.91 (s, 0.45H), 7.57-7.48 (m, 0.4H),7.44-7.29 (m, 2H), 7.30-7.21 (m, 1H), 7.21-7.13 (m, 0.8H), 6.72 (s,0.6H), 6.36-6.25 (m, 1H), 5.34 (s, 0.2H), 4.78-4.69 (m, 0.8H), 4.61 (d,J=5.2 Hz, 0.2H), 4.28 (s, 0.8H), 4.12 (s, 0.2H), 4.05-3.95 (m, 1H),2.17-1.41 (m, 6H).

Example 295(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 279 substituting intermediate A-2 withintermediate A-24. MS (ESI) mass calcd. for: C₂₂H₂₁F₃N₆O, 442.1 m/zfound 443.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.32 (s, 0.2H), 8.23(s, 0.8H), 7.90 (s, 1.55H), 7.85 (s, 0.45H), 7.57-7.25 (m, 3.2H),7.24-7.15 (m, 0.8H), 6.93 (s, 0.8H), 6.38-6.27 (m, 1H), 5.22 (s, 0.2H),4.74-4.65 (m, 0.8H), 4.55 (d, J=4.7 Hz, 0.2H), 4.28 (s, 0.8H), 4.09 (s,0.2H), 4.03-3.95 (m, 1H), 2.20 (s, 3H), 2.13-1.38 (m, 6H).

Example 296(3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 279 substituting intermediate A-2 withintermediate A-31. MS (ESI) mass calcd. for: C₂₃H₂₁F₃N₄O₂, 442.2 m/zfound 443.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.19 (s, 1H),7.91-7.80 (m, 2H), 7.32-7.21 (m, 4H), 7.19-7.13 (m, 1H), 6.32 (d, J=8.8Hz, 1H), 4.79-4.72 (m, 1H), 4.36-4.28 (m, 1H), 3.93 (d, J=4.6 Hz, 1H),2.29 (s, 3H), 2.10 (dd, J=12.9, 8.1 Hz, 1H), 2.00-1.85 (m, 2H),1.76-1.64 (m, 2H), 1.55-1.46 (m, 1H).

Example 297(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1R,2S,4S)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate B-5 withintermediate B-8. MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.2; m/z found459.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.91-8.84 (m, 2H), 8.27 (s,1H), 8.19 (s, 1H), 7.65 (d, J=1.4 Hz, 1H), 7.44-7.34 (m, 2H), 7.24-7.16(m, 2H), 4.77-4.68 (m, 1H), 4.43-4.33 (m, 1H), 4.07 (d, J=5.1 Hz, 1H),2.16 (dd, J=13.0, 8.2 Hz, 1H), 2.10-1.99 (m, 1H), 1.98-1.86 (m, 1H),1.78-1.65 (m, 2H), 1.58-1.48 (m, 1H).

Example 298(3-fluoro-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 299(3-methyl-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 300(3-chloro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 301((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

Example 302((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(oxazol-2-yl)phenyl)methanone

Example 303((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Example 304((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Example 305((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 306((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 307((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

Example 308((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(oxazol-2-yl)phenyl)methanone

Example 309((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Example 310((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Example 311((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 312((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

Example 313((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

Example 314((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(oxazol-2-yl)phenyl)methanone

Example 315((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Example 316((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Example 317((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 318((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 319(3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 320(3-fluoro-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 321(3-fluoro-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 322(3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 323(3-fluoro-2-(pyridin-2-yl)phenyl)((2S)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 324(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 325(2-methoxy-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 326(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 327 (4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 328(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 329(5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 330(2-fluoro-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 331(2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 332(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 333(3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 334(3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 335(2-(5-fluoropyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 336(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 337 (5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 338(2-bromo-3-fluorophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 339(3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 340(2-methoxy-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 341(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 342(4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 343(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 344(5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 345(2-fluoro-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 346(2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 347(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 348(3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 349(3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 350(2-(5-fluoropyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 351(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 352(5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 353(2-bromo-3-fluorophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 354 (2-methoxy-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 355(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 356(4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 357(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 358(5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 359(2-fluoro-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 360(2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 361(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 362(3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 363(3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 364(2-(5-fluoropyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 365(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 366(5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 367(2-bromo-3-fluorophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Assays

The in vitro affinity of the compounds of the invention for therat/human orexin 1 and human orexin 2 receptors was determined bycompetitive radioligand binding using [3H](1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone)(Langmeadet al., 2004) and [3H]EMPA(n-ethyl-2[96-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethylacetamide), respectively (Langmead et al., 2004, British Journal ofPharmacology 141:340-346; Malherbe et al., 2004, British Journal ofPharmacology 156:1326-41).

The in vitro functional antagonism of the compounds on the human orexin1 and orexin 2 receptors was determined using fluorometric imaging platereader (FLIPR) based calcium assays.

Rat and Human Orexin 1 Receptor Radioligand Binding Studies

Human Embryonic Kidney 293 cells (HEK293) stably expressing rat orexin 1receptor (Genebank accession number NM_001525) or Chinese ovary cells(CHO) stably expressing human orexin 1 receptor (Genebank accessionnumber NM_001526) were grown to confluency in DMEM (Hyclone, cat #SH30022), 10% FBS, 1× Pen/Strep, 1× sodium pyruvate, 10 mM HEPES, 600μg/mL G418 and DMEM/F₁₂ (Gibco, Cat #11039), 10% FBS, 1× Pen/Strep, 600μg/mL G418 media, respectively on 150 cm2 tissue culture plates, washedwith 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1×with Calcium and Magnesium, Cat # SH30264.01, hereafter referred tosimply as PBS) and scraped into 50 ml tubes. After centrifugation (2K×G,5 min at 4° C.), the supernatant was aspirated and the pellets frozenand stored at −800 C. Cells were resuspended in PBS in the presence of 1tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, storedon ice, and homogenized for 45 sec prior to addition to the reactions.Competition binding experiments in 96 well polypropylene plates wereperformed using [3H]-SB674042 (Moraveck Corporation, specificactivity=35.3 Ci/mmol), diluted to a 10 nM concentration in PBS (4 nMfinal). Compounds were solubilized in 100% DMSO (Acros Organics, Cat.#61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to10 μM). The final concentration of DMSO in the reactions is equal to orless than 0.1%. Total and nonspecific binding was determined in theabsence and presence of 10 μM almorexant. The total volume of eachreaction is 200 μL (20 μL of diluted compounds, 80 μL of[³H]-(1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone)diluted in PBS and 100 μL of the cell suspension). Reactions were runfor 60 min at room temperature and terminated by filtration through GF/Cfilter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3%polyethylenimine using the cell harvester (PerkinElmer Filtermate). Theplates were washed 3 times by aspirating 30 ml PBS through the plates.Plates were dried in 55° C. oven for 60 min, scintillation fluid wasadded, and the radioactivity was counted on a Topcount (Packard).

IC₅₀ values (i.e. concentration of unlabelled compound required tocompete for 50% of specific binding to the radioligand) was calculatedusing the GraphPad Prism software (GraphPad Prism Software Inc., SanDiego, Calif.) with a fit to a sigmoidal dose-response curve. ApparentKi values were calculated as Ki=IC₅₀/(1+C/Kd), where C is concentrationof radioligand and Kd=4 nM for rat orexin 1 receptor and 6 nM for humanorexin 1 receptor.

Human Orexin 2 Receptor Radioligand Binding Studies

HEK293 stably expressing human orexin 2 receptor (Genebank accessionnumber NM_001526) were grown to confluency in DMEM (Hyclone, cat #SH30022), 10% FBS, 1× Pen/Strep, 1× NaPyruvate, 10 mM HEPES, 600 g/mlG418 media on 150 cm² tissue culture plates, washed with 5 mM EDTA inPBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium andMagnesium, Cat # SH30264.01, hereafter referred to simply as PBS) andscraped into 50 ml tubes. After centrifugation (2K xG, 5 min at 40° C.),the supernatant was aspirated and the pellets frozen and stored at −800°C. Cells were resuspended in PBS in the presence of 1 tablet of proteaseinhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cellpellet from a 15 cm plate was resuspended in 10 mL, stored on ice, andhomogenized for 45 sec just prior to addition to the reactions.Competition binding experiments in 96 well polypropylene plates wereperformed using [3H]-EMPA (Moraveck Corporation, specific activity=29.6Ci/mmol), diluted to a 5 nM concentration in PBS (2 nM finalconcentration). Compounds were solubilized in 100% DMSO (Acros Organics,Cat. #61042-1000) and tested over a range of 7 concentration (from 0.1nM to 10 μM). The final concentration of DMSO in the reactions is equalto or less than 0.1%. Total and nonspecific binding was determined inthe absence and presence of 10 μM almorexant. The total volume of eachreaction is 200 μL (20 μL of diluted compounds, 80 μL of [3H]-EMPAdiluted in PBS and 100 μL of the cell suspension). Reactions were runfor 60 min at room temperature and terminated by filtration through GF/Cfilter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3%polyethylenimine using the cell harvester (PerkinElmer Filtermate). Theplates were washed 3 times by aspirating 30 ml PBS through the plates.Plates were dried in 55° C. oven for 60 min, scintillation fluid wasadded, and the radioactivity was counted on a Topcount (Packard).

IC₅₀ values (i.e. concentration of unlabelled compound required tocompete for 50% of specific binding to the radioligand) was calculatedusing the GraphPad Prism software (GraphPad Prism Software Inc., SanDiego, Calif.) with a fit to a sigmoidal dose-response curve. ApparentKi values were calculated as Ki=IC₅₀/(1+C/Kd), where C is concentrationof radioligand and Kd=2 nM.

Human Orexin 1 Receptor Ca2+ Mobilization Assay

CHO cells stably transfected with the human orexin 1 receptor (Genebankaccession number NM_001526) were grown to confluency in DMEM/F12, 10%FBS, 1× pen-strep, 400 g/ml G418. Cells were seeded on to 384-wellPackard viewplates at a density of 10,000 cells/well and incubatedovernight at 370 C, 5% CO₂. The cells were dye-loaded with BD CalciumAssay kit (BD, cat #640178) in HBSS (Gibco, cat#14025-092) with 2.5 mMprobenecid and incubated at 37° C., 5% CO2 for 45 min. Cells werepre-incubated with compounds (diluted in DMEM/F-12) for 15-30 minutesbefore agonist (orexin A, 10 nM) stimulation. Ligand-induced Ca²⁺release was measured using a Fluorometric Imaging Plate Reader (FLIPR,Molecular Devices, Sunnyvale, Calif.). Functional responses weremeasured as peak fluorescence intensity minus basal. The concentrationof agonist that produced a half-maximal response is represented by theEC₅₀ value. Antagonistic potency values were converted to apparent pKBvalues using a modified Cheng-Prusoff correction. Apparent pKB=−logIC₅₀/1+[conc agonist/EC₅₀]. Data are expressed as mean±S.E.M.

Human Orexin 2 Receptor Ca2+ Mobilization Assay

PFSK-1 cells endogenously expressing the human orexin 2 receptor weregrown to confluency in RPMI1640 (Hyclone, cat#30027.02), 10% FBS, 1×pen-strep. Cells were seeded on to 384-well Packard viewplates at adensity of 5,000 cells/well and incubated overnight at 370 C, 5% CO₂.The cells were dye-loaded with BD Calcium Assay kit (BD, cat #640178) inHBSS (Gibco, cat#14025-092) with 2.5 mM probenecid and incubated at 37°C., 5% CO2 for 45 min. Cells were pre-incubated with compounds (dilutedin DMEM/F-12) for 15-30 minutes before agonist (orexin B, 100 nM)stimulation. Ligand-induced Ca²⁺release was measured using aFluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale,Calif.). Functional responses were measured as peak fluorescenceintensity minus basal. The concentration of agonist that produced ahalf-maximal response is represented by the EC₅₀ value. Antagonisticpotency values were converted to apparent pKB values using a modifiedCheng-Prusoff correction. Apparent pKB=−log IC₅₀/1+[conc agonist/EC50].Data are expressed as mean±S.E.M.

Preferred compounds of the invention are set forth in the table below.Orexin receptor activity of certain compounds of the invention is alsoset forth in the below table.

rOX1 hOX1 hOX2 Ex. K_(i) K_(i) K_(i) Compound No. Compound (nm) (nm)(nm) Name  1

25 41 276 (5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)-2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 2

31 23 500 (±)-(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 3A

24 19 268 (6-methyl-3- (pyrimidin-2- yl)pyridin-2- yl)((1S*,2R*,4R*)-2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 3B

>10000 >10000 (6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)((1R*,2S*,4S*)-2- ((pyridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone  4

36 41 927 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 5A

14 15 428 (6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicydo[2.2.1]heptan-7-yl)methanone  5B

>10000 >10000 (6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)((1R,2S,4S)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  6

14 15 428 (6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  7

19 19 198 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone  8A

9 14 94 ((1S,2R,4R)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone  8B

>10000 >10000 ((1R,2S,4S)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone  9

9 57 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone  10A

4 3 32 ((1S,2R,4R)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone  10B

3937 3200 5148 ((1R,2S,4S)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone  11

10 12 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-(thiophen-2- yl)phenyl)methanone  12A

177 339 ((1S*,2R*,4R*)-2- (((5-fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-(thiophen-2- yl)phenyl)methanone  12B

3 5 ((1R*,2S*,4S*)-2- (((5-fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-(thiophen-2- yl)phenyl)methanone  13

118 109 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7-azabicyclo[2.2.1]heptan- 7-yl)methanone  14

50 71 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-(trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  15

56 120 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((3-(trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  16

20 42 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6-(trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  17

41 69 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((4-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  18

12 44 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  19

12 44 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  20

270 364 (±)-(2-(((3,6- dimethylpyrazin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone  21

300 487 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((3-(trifluoromethyl) quinoxalin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone  22

47 50 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- (((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  23

322 1500 (±)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(quinolin-8- yl)methanone  24

122 164 (±)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(naphthalen-1- yl)methanone  25

74 160 (±)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2- methylnaphthalen-1- yl)methanone  26

117 394 (±)-2-(1H-pyrazol-1- yl)phenyl)(2-(((5- fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  27

677 380 (±)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-phenylfuran- 2-yl)methanone  28

14 11 (±)-(2- ethoxynaphthalen-1- yl)(2-(((5- fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  29

11 60 (±)-(5-(2- fluorophenyl)-2- methylthiazol-4-yl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  30

47 149 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  31

33 122 (±)-(2-fluoro-6- (pyrimidin-2- yl)phenyl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  32

21 123 (±)-(5-fluoro-2- (pyrimidin-2- yl)phenyl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  33

15 9 39 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone  34

60 467 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((quinoxalin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  35

69 58 693 (±)-(2-fluoro-6-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 36

70 107 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 37

300 487 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 38

120 383 (±)-(5-methyl-2- (pyrimidin-2- yl)phenyl)(2- ((quinoxalin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  39

29 27 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone  40

5000 1203 (±)-2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-5- phenylisoxazol-4-yl)methanone  41

35 22 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2- ethoxynaphthalen-1- yl)methanone  42

1277 253 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2- ethoxyphenyl)methanone)  43

222 92 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-fluoro-6- (pyrimidin-2-yl)phenyl)methanone  44

400 104 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-fluoro-2- (pyrimidin-2-yl)phenyl)methanone  45

79 59 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (pyrimidin-2-yl)phenyl)methanone  46

82 10 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-(thiophen-2- yl)phenyl)methanone  47

460 418 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (((5-(trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  48

3900 4700 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- (((5-(trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  49

81 69 192 (±)-(2-(((5- bromopyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone  50

460 4399 (±)-(2-(((5- bromopyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- methoxyphenyl)methanone  51

974 1800 (±)-(2-(((5- bromopyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-ethoxy-6- methylpyridin-2- yl)methanone 52

350 2300 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  53

2200 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyridazin-3- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 54

3500 2200 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-(((2-methylpyridin-3- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  55

119 150 202 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-(((3-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  56

>10000 >10000 (±)-(2-(((1-methyl-1H- pyrazol-5- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone  57

1000 7300 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyridin-4- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 58

88 117 2400 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyridin-3- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 59

2600 4900 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyrimidin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 60

7800 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyrazin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 61

2800 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyrimidin-4- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 62

74 46 188 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-(((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  63

25 25 339 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (oxazol-2-yl)pyridin-2-yl)methanone  64

18 24 81 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)methanone  65

1440 6200 (±)-(3,6′-dimethyl- [2,3′-bipyridin]-2′- yl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  66

197 293 620 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(3- methyl-1,2,4- oxadiazol-5-yl)pyridin-2- yl)methanone  67

48 69 258 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(3- methyl-1H-pyrazol-1-yl)pyridin-2- yl)methanone  68

27 22 576 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrrolidin-1- yl)pyridin-2-yl)methanone  69

40 64 174 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(3- methylisoxazol-5-yl)pyridin-2- yl)methanone  70

88 62 624 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (1H-pyrazol-1- yl)pyridin-2-yl)methanone  71

1200 3700 (±)-(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 72

137 162 2400 (±)-(4-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 73

278 7900 (±)-(3- (dimethylamino)-6- methylpyridin-2-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  74

359 1700 (±)-(3-(2H-1,2,3- triazol-2-yl)quinolin- 2-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  75

18 7 220 (±)-(7-ethoxyquinolin- 8-yl)(2-((pyridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone  76

>10000 >10000 (±)-(3,6- dimethylimidazo[1,2- a]pyridin-5-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 77

103 66 867 (±)-(1-methyl-4- phenyl-1H-pyrazol-3- yl)((1S,2R,4R)-2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 78

418 3100 (±)-(1-methyl-3- phenyl-1H-pyrazol-4- yl)((1S,2R,4R)-2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 79

2400 8500 (±)-((3,7- dimethylimidazo[1,2- a]pyridin-8-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 80

1100 >10000 (±)-(7- methylimidazo[1,2- a]pyridin-8-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  81

916 2900 (±)-(1-methyl-4- phenyl-1H-pyrazol-5- yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  82

>10000 >10000 (±)-((6- methylimidazo[1,2- a]pyridin-5-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 83

17 12 271 (±)-(3- ethoxyisoquinolin-4- yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  84

2600 9701 (±)-(1-methyl-5- phenyl-1H-pyrazol-4- yl)(-2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  85

>10000 >10000 (±)-(6-methyl-3-(4- methylpiperazin-1- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 86

>10000 >10000 (±)-(6-methyl-3- (piperazin-1- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 87

4200 >10000 (±)-(6-methyl-3- morpholinopyridin-2- yl)((1S,2R,4R)-2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 88

47 49 690 (±)-(7- methoxyquinolin-8- yl)(2-((pyridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone  89

11 10 38 (±)-(2- ethoxynaphthalen-1- yl)(2-((pyridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone  90

3000 >10000 (±)-(3,6′-dimethyl- [2,3′-bipyridin]-2′- yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  91

624 3300 (±)-(3-(2H-1,2,3- triazol-2-yl)pyridin-2- yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  92

20 11 218 (±)-(2-methyl-5- phenylthiazol-4-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  93

40 73 836 (±)-(6-methyl-3- (oxazol-2-yl)pyridin- 2-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  94

170 200 2100 (±)-(6-methyl-3-(3- methylisoxazol-5- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 95

247 3700 (±)-(6-methyl-3-(1H- pyrazol-1-yl)pyridin- 2-yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  96

70 76 950 (±)-(6-methyl-3-(4- methyl-1H-pyrazol-1- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 97

35 32 840 (±)-(6-methyl-3- (pyrrolidin-1- yl)pyridin-2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 98

>10000 >10000 (±)-(3,6′-dimethyl- [2,3′-bipyridin]-2′- yl)(2-(((5-fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone  99

1500 2900 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(3- methylisoxazol-5-yl)pyridin-2- yl)methanone 100

950 1800 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (oxazol-2-yl)pyridin-2-yl)methanone 101

650 1200 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrrolidin-1- yl)pyridin-2-yl)methanone 102

(±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)methanone 103

1700 3600 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(4- methyl-1H-pyrazol-1-yl)pyridin-2- yl)methanone 104

1100 4600 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (1H-pyrazol-1- yl)pyridin-2-yl)methanone 105

(±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 106

300 154 (±)-(2,6- dimethoxyphenyl)(2- (((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 107

440 2200 (±)-((3-fluoro-2- methoxyphenyl)(2- (((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 108

10 12 12 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-methoxy-6- (2H-1,2,3-triazol-2-yl)phenyl)methanone 109

29 20 99 (±)-(5-fluoro-2-(1H- pyrazol-5- yl)phenyl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 110

54 67 94 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-methyl-6- (2H-1,2,3-triazol-2-yl)phenyl)methanone 111

19 19 198 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone 112

480 1000 (±)-(5-chloro-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 113

3400 4800 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methoxy-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone 114

20 48 73 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-methoxy-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 115

57 78 108 (±)-(2-fluoro-6-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 116

142 250 315 (±)-(4-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 117

62 82 245 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 118

440 2200 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- (((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 119

500 1300 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(4-methoxy-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 120

15 14 124 (±)-(5-chloro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 121

78 68 340 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(4-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 122

118 154 1000 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(4-methyl-2- (pyrimidin-2-yl)phenyl)methanone 123

400 286 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]hepta n-7-yl)(2-methyl-6- (pyrimidin-2-yl)phenyl)methanone 124

83 52 355 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(-2-(((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 125

47 29 132 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 126

23 27 231 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5- (hydroxymethyl)-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone 127

190 1100 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 128

5700 10000 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone129

190 1000 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 130

3700 7199 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone131

10000 10000 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-(((4- (trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7-azabicyclo[2.2.1]heptan- 7-yl)methanone 132

10000 7399 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2-(((4- (trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7-azabicyclo[2.2.1]heptan- 7-yl)methanone 133

1400 950 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7-azabicyclo[2.2.1]heptan- 7-yl)methanone 134

1500 690 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7-azabicyclo[2.2.1]heptan- 7-yl)methanone 135

5400 3900 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-(((5-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 136

6800 1200 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2-(((5-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 137

950 425 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-(((5-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 138

606 250 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 139

4399 6500 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-(((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 140

3100 2300 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2-(((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 141

280 300 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-(((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 142

207 300 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 143

3900 4600 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-(((6- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 144

3600 3200 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2-(((6- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 145

340 330 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-(((6-(trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 146

180 196 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6-(trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 147

(±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone148

6299 3200 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone149

220 2000 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone150

180 990 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone151

10000 10000 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-2- (2H-1,2,3-triazol-2-yl)pyridin-3- yl)methanone 152

10000 5899 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-2- (1H-1,2,3-triazol-1-yl)pyridin-3- yl)methanone 153

1100 440 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-(3-methyl- 1,2,4-oxadiazol-5-yl)phenyl)methanone 154

690 300 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 155

1570 3600 (±)-(2-ethoxy-4- methylpyridin-3-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 156

>10000 >10000 (±)-(6- methylimidazo[2,1- b]thiazol-5-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 157

94 134 537 (±)-(5-bromo-2- ethoxypyridin-3-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 158

2930 1780 (±)-(2-ethoxy-6- methylpyridin-3-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 159

262 786 (±)-(7- hydroxyquinolin-8- yl)(2-((pyridin-2- yloxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 160

8700 >10000 (±)-(2-ethoxy-5- phenylpyridin-3-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 161

478 1450 (±)-(4-bromo-2- ethoxypyridin-3-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 162

8500 >10000 (±)-(2-chloro-4- ethoxypyridin-3-yl)(2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 163

150 153 150 (±)-(2,4- diethoxypyridin-3- yl)(2-((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 164

9 7 195 (3-ethoxyisoquinolin- 4-yl)((1S,2R,4R)-2- ((pyridin-2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 165

409 550 (±)-(2- ethoxyphenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 166

106 1141 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone167

9 14 (±)-5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 168

2300 7300 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone169

8999 2526 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((pyridin-2-ylamino)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 170

1965 512 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)amino)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-fluoro-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 171

1935 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin- 2- yl)amino)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 172

686 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6-(trifluoromethyl)pyridin- 2-yl)amino)methyl)- 7-azabicyclo[2.2.1]heptan- 7-yl)methanone 173

1260 3000 (±)-(3-fluoro-2- methoxyphenyl)(2- (((5-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 174

373 1000 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((quinoxalin-2- ylamino)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 175

2500 4000 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)methanone 176

119 150 202 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-(((3-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 177

535 4000 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(4- methyloxazol-2-yl)pyridin-2- yl)methanone 178

964 >10000 (6-methyl-3-(4- methyloxazol-2- yl)pyridin-2-yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 179

((1S,2R,4R)-2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(4- methyloxazol-2-yl)pyridin-2- yl)methanone 180

33 32 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6- methyl-2-(trifluoromethyl)pyrimidin- 4-yl)oxy)methyl)- 7-azabicyclo[2.2.1]heptan- 7-yl)methanone 181

34 28 700 (2-(2H-1,2,3-triazol-2- yl)phenyl)(1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 182

47 38 1100 (±)-((2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 183a

>10000 >10000 (2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 183b

34 28 700 (2-(2H-1,2,3-triazol-2- yl)phenyl)((1R,2S,4S)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 184

189 349 4100 (±)-(5-methyl-3-(2H- 1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 185

1500 2700 (±)-(5-methyl-3-(1H- 1,2,3-triazol-1- yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 186

134 164 1200 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 187

81 48 620 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 188

295 1500 (±)-(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 189

766 1500 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 190

589 1200 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 191

257 8800 (±)-(4-methoxy-2- (2H-1,2,3-triazol-2- yl)phenyl)(2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 192

60 52 1500 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 193

2900 >10000 (±)-((3-fluoro-2- methoxyphenyl)(2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 194

450 800 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- ((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 195

57 37 325 (±)-(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 196

59 61 1500 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 197

8999 862 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(5-fluoro-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 198

1411 704 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(2-fluoro-6- (2H-1,2,3-triazol-2-yl)phenyl)methanone 199

1634 553 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(4-fluoro-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 200

1100 552 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)methanone 201

3700 1100 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone 202

760 444 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((4,6-dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 203

>10000 490 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]hepta n-7-yl)(3-ethoxy-6- methylpyridin-2- yl)methanone204

33 25 220 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- (quinoxalin-2-ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 205

79 50 168 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-(quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 206

1200 1500 (±)-(3-fluoro-2- methoxyphenyl)(2- (quinoxalin-2- ylamino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 207

120 95 64 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- (quinoxalin-2-ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 208

26 30 90 (±)-(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)(2-(quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 209

1100 736 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((6-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 210

211 128 (±)-((2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((4-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 211

110 55 1800 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2-((5-chloropyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 212

734 4900 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((6-(trifluoromethyl)pyridazin- 3-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 213

2800 7501 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2-((5-methoxypyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 214

500 3100 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5-methylpyridin-2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 215

1700 8999 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2-(pyridin-2-ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 216

99 71 475 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5-chlorobenzo[d]oxazol- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 217

59 40 770 (±)-(2-((5- bromopyridin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)methanone 218

2700 6700 (±)-(2-((5- bromopyridin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- methoxyphenyl)methanone 219

257 1700 (±)-(2-((5- bromopyridin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-ethoxy-6- methylpyridin-2- yl)methanone220

38 26 1100 (±)-(2-((5- bromopyridin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone 221

172 200 3300 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 222

4800 >10000 (±)-(3-fluoro-2- methoxyphenyl)(2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 223

550 4000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 224

2500 7399 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- ((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 225

530 3300 (±)-(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 226

>10000 >10000 (±)-(3-fluoro-2- methoxyphenyl)(2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 227

>10000 >10000 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- ((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 228

>10000 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 229

>10000 >10000 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- (quinoxalin-2-ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 230

>10000 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-(quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 231

>10000 >10000 (±)-(3-fluoro-2- methoxyphenyl)(2- (quinoxalin-2-ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 232

(±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone 233

(±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6- methylpyridin-2- yl)methanone 234

(±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2- methoxyphenyl)methanone 235

>10000 >10000 (±)-((2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((4-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 236

>10000 >10000 (±)-(2-((5- fluoropyridin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2-yl)pyridin-2- yl)methanone 237

>10000 >10000 (±)-(3-fluoro-2- methoxyphenyl)(2-((5- fluoropyridin-2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 238

16 16 955 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 239

22 19 490 (2-ethoxynaphthalen- 1-yl)((1S,2R,4R)-2- ((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 240

400 2100 isoquinolin-4- yl((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin-2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 241

134 159 5064 (4-methoxy-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 242

31 41 239 (2-methoxy-6-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 243

34 45 723 (5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 244

74 46 235 (5-(4-fluorophenyl)-2- methylthiazol-4- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 245

10 7 288 (3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 246

29 17 1022 (3-ethoxyisoquinolin- 4-yl)((1S,2R,4R)-2- ((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 247

420 1130 (6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 248

153 119 >10000 (6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 249

57 54 5600 (4-methoxy-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 250

5649 >10000 (1H- benzo[d]imidazol-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 251

520 5300 (1-methyl-1H- benzo[d]imidazol-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 252

45 27 1230 (3-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 253

155 152 9601 (4-(difluoromethoxy)- 2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 254

23 20 377 (3-fluoro-2-(3-methyl- 1,2,4-oxadiazol-5-yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 255

32 29 265 (5-methoxy-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 256

84 60 1100 (5-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 257

85 102 3200 (4-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 258

42 48 690 (2-fluoro-6-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 259

>10000 >10000 (6-methylimidazo[2,1- b]thiazol-5- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 260

14 10 519 (3-fluoro-2-(oxazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 261

>10000 5000 (2-((4,6- dimethylpyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- methoxyphenyl)methanone 262

106 175 4200 (3-fluoro-2-(pyridazin- 3- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 263

44 41 1100 (3-methyl-2- (pyridazin-3- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 264

1400 >10000 (3-fluoro-2-(pyridazin- 4- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 265

20 23 188 (3-fluoro-2-(pyrazin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 266

5 7 121 (3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 267

33 61 1700 (4-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 268

450 3700 (3-fluoro-2-(pyridin-4- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 269

48 111 1700 (3-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 270

325 145 ((1S,2R,4R)-2-((3- bromoimidazo[1,2- a]pyrazin-8-yl)amino)- 7-azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (pyrimidin-2-yl)phenyl)methanone 271

41 42 2300 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 272

21 26 742 (3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 273

17 12 328 (3-methyl-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 274

>10000 2560 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((3-(trifluoromethyl)- [1,2,4]triazolo[4,3- a]pyrazin-8-yl)amino)- 7-azabicyclo[2.2.1]heptan- 7-yl)methanone 275

>10000 >10000 methyl 5- (((1S,2R,4R)-7-(3- fluoro-2-(pyrimidin-2-yl)benzoyl)-7- azabicyclo[2.2.1]heptan- 2- yl)amino)pyrazine-2-carboxylate 276

133 97 2500 (2-iodo-3- methylphenyl)((1S,2R, 4R)-2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 277

457 7399 (3-fluoro-2- iodophenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 278

87 77 934 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)-2-((5-methylpyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 279

15 8 1100 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 280

39 37 1300 (4-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 281

21 17 1200 (3-methyl-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 282

486 >10000 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)-2-(methyl(5- (trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 283

14 9 417 (3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 284

29 27 1700 (3-fluoro-2-(oxazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 285

720 >10000 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 286

>10000 >10000 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 287

472 767 (3-ethoxy-6- methylpyridin-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 288

94 128 1900 (3-(2H-1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 289

13 32 173 (2-methoxy-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 290

21 19 558 (2-fluoro-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 291

15 35 425 (7-ethoxyquinolin-8- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 292

>10000 >10000 (2-(1,4-dimethyl-1H- pyrazol-5-yl)-6- methoxyphenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)methanone 293

23 37 1100 (3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 294

21 15 1200 (3-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 295

9 8 257 (3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 296

5 6 114 (3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 297

>10000 >10000 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1R,2S,4S)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 298

(3-fluoro-2-(oxazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 299

(3-methyl-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 300

(3-chloro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 301

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2- (oxazol-2- yl)phenyl)methanone 302

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2- (oxazol-2- yl)phenyl)methanone 303

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2- (pyrimidin-2- yl)phenyl)methanone 304

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2- (pyrimidin-2- yl)phenyl)methanone 305

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 306

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 307

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2- (oxazol-2- yl)phenyl)methanone 308

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2- (oxazol-2- yl)phenyl)methanone 309

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2- (pyrimidin-2- yl)phenyl)methanone 310

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2- (pyrimidin-2- yl)phenyl)methanone 311

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 312

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 313

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (oxazol-2-yl)phenyl)methanone 314

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (oxazol-2-yl)phenyl)methanone 315

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (pyrimidin-2-yl)phenyl)methanone 316

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (pyrimidin-2-yl)phenyl)methanone 317

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 318

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7-azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone 319

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 320

(3-fluoro-2-(pyridin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 321

(3-fluoro-2-(pyridin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 322

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 323

(3-fluoro-2-(pyridin-2- yl)phenyl)((2S)-2-((5- (trifluoromethyl)pyrazin-2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 324

(3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 325

(2-methoxy-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 326

(5-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 327

(4-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 328

(3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 329

(5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 330

(2-fluoro-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 331

(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 332

(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 333

(3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 334

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 335

(2-(5-fluoropyrimidin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 336

(2-fluoro-6-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 337

(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 338

(2-bromo-3- fluorophenyl)((1S,2R, 4R)-2-((5- (trifluoromethyl)pyridin-2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 339

(3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 340

(2-methoxy-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 341

(5-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 342

(4-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 343

(3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 344

(5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 345

(2-fluoro-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 346

(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 347

(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 348

(3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 349

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 350

(2-(5-fluoropyrimidin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 351

(2-fluoro-6-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 352

(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 353

(2-bromo-3- fluorophenyl)((1S,2R, 4R)-2-((5- (trifluoromethyl)pyrazin-2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 354

(2-methoxy-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 355

(5-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 356

(4-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 357

(3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 358

(5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 359

(2-fluoro-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 360

(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 361

(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 362

(3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 363

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 364

(2-(5-fluoropyrimidin- 2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 365

(2-fluoro-6-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 366

(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan-7-yl)methanone 367

(2-bromo-3- fluorophenyl)((1S,2R, 4R)-2-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone

1. (canceled)
 2. A compound of the Formula (I):

or an enantiomer, diastereomer, tautomer, or isotopic variant thereof;or a pharmaceutically acceptable salt or solvate thereof; wherein: R₁ isH; R₂ is H; ring A is:

X is CR₆ and Y is CR₇; R₆ is H or pyrimidinyl; R₇ is H or halo; R₃ is Hor pyrimidinyl; R₄ is H or halo; Z is NH; R₅ is optionally substitutedpyrazinyl.
 3. The compound of claim 2, wherein n is
 1. 4. The compoundof claim 2, wherein R₆ is H.
 5. The compound of claim 2, wherein R₆ ispyrimidinyl.
 6. The compound of claim 2, wherein R₇ is H.
 7. Thecompound of claim 2, wherein R₇ is halo.
 8. The compound of claim 7,wherein R₇ is F, Cl, or Br.
 9. The compound of claim 2, wherein R₃ is H.10. The compound of claim 2, wherein R₃ is pyrimidinyl.
 11. The compoundof claim 2, wherein R₄ is H.
 12. The compound of claim 2, wherein R₄ ishalo.
 13. The compound of claim 12, wherein R₄ is F, Cl, or Br.
 14. Thecompound of claim 13, wherein R4 is F.
 15. The compound of claim 2,wherein R₅ is substituted with one trihaloalkyl.
 16. The compound ofclaim 15, wherein R₅ is substituted with one trifluoromethyl.
 17. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 1 and at least one pharmaceuticallyacceptable excipient.
 18. A method of treating a disease, disorder, ormedical condition, wherein the disease, disorder, or medical conditionis a sleep disorder, a metabolic disorder, a neurological disorder, anarrhythmia, acute heart failure, an ulcer, irritable bowel syndrome,diarrhea, gastroesophageal reflux, a mood disorder, post-traumaticstress disorder, a panic disorder, attention deficit disorder, cognitivedeficiency, or substance abuse, comprising administering a compound ofclaim 1 to a patient in need thereof.
 19. The method of claim 18,wherein the disease, disorder, or medical condition is a mood disorder,post-traumatic stress disorder, panic disorder, attention deficitdisorder, cognitive deficiency, or substance abuse.
 20. The method ofclaim 18, wherein the disease, disorder, or medical condition ispost-traumatic stress disorder or a panic disorder.
 21. The method ofclaim 18, wherein the sleep disorder is a sleep-wake transitiondisorder, insomnia, restless legs syndrome, jet-lag, disturbed sleep, ora sleep disorder secondary to neurological disorders.
 22. The method ofclaim 18, wherein the metabolic disorder is overweight, obesity, insulinresistance, type II diabetes, hyperlipidemia, a gallstone, angina,hypertension, breathlessness, tachycardia, infertility, sleep apnea,back and joint pain, a varicose vein, or osteoarthritis.
 23. The methodof claim 18, wherein the neurological disorder is Parkinson's disease,Alzheimer's disease, Tourette's syndrome, catatonia, anxiety, delirium,or dementia.